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J Cereb Blood Flow Metab. Jul 2011; 31(7): 1554–1571.
Published online May 11, 2011. doi:  10.1038/jcbfm.2011.70
PMCID: PMC3137480

Vascular plasticity in cerebrovascular disorders

Abstract

Cerebral ischemia remains a major cause of morbidity and mortality with little advancement in subacute treatment options. This review aims to cover and discuss novel insight obtained during the last decade into plastic changes in the vasoconstrictor receptor profiles of cerebral arteries and microvessels that takes place after different types of stroke. Receptors like the endothelin type B, angiotensin type 1, and 5-hydroxytryptamine type 1B/1D receptors are upregulated in the smooth muscle layer of cerebral arteries after different types of ischemic stroke as well as after subarachnoid hemorrhage, yielding rather dramatic changes in the contractility of the vessels. Some of the signal transduction processes mediating this receptor upregulation have been elucidated. In particular the extracellular regulated kinase 1/2 pathway, which is activated early in the process, has proven to be a promising therapeutic target for prevention of vasoconstrictor receptor upregulation after stroke. Together, those findings provide new perspectives on the pathophysiology of ischemic stroke and point toward a novel way of reducing vasoconstriction, neuronal cell death, and thus neurologic deficits after stroke.

Keywords: cerebral blood vessels, contractile receptors, ischemia, protein kinases, transcriptional regulation

Introduction

Stroke is the third leading cause of death worldwide after ischemic heart disease and all types of cancer combined (Warlow et al, 2003). Recent statistics of the American Heart Association reveals that stroke accounts for one of every 17 deaths in the United States (Lloyd-Jones et al, 2009). With the growing elderly population, stroke prevalence and stroke-related costs steadily increase.

There are two major types of stroke: (1) ischemic stroke, which occurs when the blood supply to the entire brain (e.g., during a cardiac arrest) or a circumscribed part of the brain (e.g., by thromboembolic occlusion of a cerebral artery) is disrupted and (2) hemorrhagic stroke, which occurs when a cerebral artery leaks blood into the brain tissue (intracerebral hemorrhage) or the subarachnoid space surrounding the brain (subarachnoid hemorrhage, SAH). Despite intense basic and translational research for the last four decades, the treatments for both types of stroke are still mainly focused on prevention of new attacks by minimizing the risk factors involved and on acute relief of the cause of the stroke, such as dissolution of the thrombotic clot or closure of the bleeding cerebral artery. With regards to the longer-term pathophysiology and development of cerebral damage in the subacute period following a stroke, treatment options are few and ineffective.

Ischemic Stroke

The brain area affected by a focal ischemic stroke consists of two parts: the central ischemic core where the neurons have no chance of surviving without rapid reperfusion, and the penumbra, a perifocal area with less severe ischemia, which is potentially salvageable. Cell death in the core is caused primarily by a severe reduction in blood flow below the threshold of energy failure (Hossmann, 2009). In the subacute period following the stroke, an expansion of the ischemic core into the penumbral area is often seen. Mechanisms underlying the growth of an infarct into the periinfarct penumbra are not well understood, but it is thought to involve a gradual time-dependent increase in the threshold of energy failure and a delayed cell death caused by molecular disturbances in the neurons initiated by the acute ischemic insult (Hossmann, 2009).

With regard to treating focal ischemic stroke, two major approaches have been developed; reperfusion of the occluded artery by dissolution of the clot with a thrombolytic drug (recombinant tissue-type plasminogen activator), and administration of neuroprotective agents. Use of recombinant tissue-type plasminogen activator is limited by time constraints; it must be administered within 4.5 hours after stroke onset to reduce the risk of hemorrhagic transformation (Shobha et al, 2011; Stemer and Lyden, 2011). As regards to the neuroprotective approach, there is no lack of targets identified. A major focus has been on free radicals and oxidative damage, which are important players in excitotoxicity, apoptosis, inflammation, and neuronal cell death after ischemia and reperfusion (McCulloch and Dewar, 2001). However, at present >1,026 neuroprotective treatments have been tried, all with poor outcome in major clinical trials (O'Collins et al, 2006). With the latest failure of the free radical-trapping agent NXY-059 in acute ischemic stroke (Lees et al, 2006), the era of large stroke trials with neuroprotective agents may have come to a halt.

Subarachnoid Hemorrhage

Hemorrhagic strokes offer yet another challenge. One type of cerebral hemorrhage is SAH due to the rupture of an arterial aneurysm. The cerebral ischemia associated with SAH follows a biphasic course: first, there is an acute phase with a rapid and transient drop in cerebral blood flow (CBF) associated with the extravasation of blood and the resulting increased intracranial pressure. The acute phase carries a mortality of about 15%, which has been reduced due to aneurismal clipping/coiling operations to prevent rebleeding. However, in surviving subjects, the acute phase is often followed by a late phase of more prolonged cerebral ischemia often associated with pathological constriction of cerebral arteries known as cerebral vasospasm (CVS). This delayed cerebral ischemia is a progressive and sometimes reversible failure of cerebral perfusion that can progress to infarction and is associated with poor outcome (Hijdra et al, 1987).

The only pharmacological treatment for delayed cerebral ischemia after SAH is the calcium channel antagonist nimodipine, which is part of the standard care (Dorhout Mees et al, 2007). However, the effect is very modest, preventing bad outcome in only one of 13 treated patients (Feigin et al, 1998). Nimodipine does not affect angiographic vasospasm at the clinically used dose (Allen et al, 1983; Espinosa et al, 1984), suggesting that clinical effects are due to either direct neuroprotection or other factors, such as prevention of spreading ischemia (see below). In contrast, one of the experimental treatments tried against delayed cerebral ischemia in SAH, the endothelin receptor antagonist clazosentan, reduced angiographic vasospasm, but had no significant effect on long-term clinical outcome (Macdonald et al, 2008a). These findings prompted the search for other contributing mechanisms in delayed cerebral ischemia in addition to proximal vasospasms (Hansen-Schwartz et al, 2007; Pluta et al, 2009). Interestingly, a number of recent studies suggest that subacute changes in the vasoconstrictive machinery of the cerebral microcirculation after SAH may result in deleterious changes in the hemodynamic response to cortical spreading depolarizations occurring after SAH (Dreier et al, 2006, 2009). While coupled to vasodilatation under normal conditions, spreading depolarization can be coupled to microcirculatory vasoconstriction and ischemia after SAH (Iadecola, 2009).

Plasticity of Cerebrovascular Receptors: A Novel Aspect of the Pathophysiology of Stroke

In recent years, a novel aspect of the pathophysiology of stroke has been revealed, namely the upregulation of vasoconstrictor receptors in the smooth muscle of cerebral arteries after a stroke. These changes are detrimental since they imply a decreased perfusion of the ischemic brain area(s). Thus, whereas much stroke research has focused on the molecular mechanisms of neuronal cell death, molecular changes in the vasculature of ischemic brain areas may be equally important for the development of brain damage after a stroke. This paper reviews our current knowledge on the field of cerebrovascular receptor changes after stroke, the molecular mechanisms mediating these changes, and their potential as pharmacological targets in stroke treatment.

Receptor Changes in Experimental Stroke

The following section will discuss cerebrovascular receptor plasticity in animal stroke models: (1) permanent focal cerebral ischemia using the Tamura method (Tamura et al, 1981a, 1981b), (2) transient focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO) followed by reperfusion (Memezawa et al, 1992a), (3) transient forebrain ischemia induced by two-artery occlusion and hypovolemia (Smith et al, 1984), and (4) SAH induced by injection of blood into the ophthalmic cistern (Prunell et al, 2002).

Table 1 gives an overview of vasoconstrictor receptor changes demonstrated in various stroke models and in patients.

Table 1
Overview of cerebrovascular receptor changes demonstrated in various stroke models

Ischemic Stroke

Some of the most prominent receptors showing plasticity in cerebral arteries are the endothelin receptors. Endothelial cells produce endothelin 1 (ET-1), which mediates its vasoactive effects through two different G-protein-coupled receptors (GPCRs), the endothelin type A (ETA) receptor, and the endothelin type B (ETB) receptor (Masaki, 1995). The ETA receptors are situated on the vascular smooth muscle cells, where their activation gives rise to strong vasoconstriction. Normally, ETB receptors are located on the endothelium of cerebral vessels, where their activation results in dilatation via the release of nitric oxide (Szok et al, 2001). Thus, in freshly isolated cerebral arteries from healthy rats, ET-1 induces a strong contractile effect, while the ETB receptor specific agonist sarafotoxin 6c (S6c) does not; in fact S6c induces a dilatory response if the artery is precontracted with another vasoconstrictor, such as thromboxane. This shows that only the ETA receptor mediates vasoconstriction in normal rat cerebral arteries (Hansen-Schwartz and Edvinsson, 2000; Leseth et al, 1999).

However, ETB receptor function is altered in a rat model of focal ischemic stroke consisting of 2 hours of unilateral MCAO at a point close to the Circle of Willis, followed by reperfusion (Memezawa et al, 1992b). Isolated MCA from nonoccluded contralateral hemisphere showed no contractile response to S6c. However, the occluded ipsilateral MCA showed a strong contraction to S6c, with an average Emax (maximum contraction, calculated as percentage of the contractile capacity of K+) around 68% (Stenman et al, 2002). Furthermore, there is a significant upregulation of ETB receptor mRNA in the occluded MCA compared with the nonoccluded MCA, indicating transcriptional ETB upregulation in the occluded MCA.

Since ETB receptors located on endothelial cells normally mediate a dilatory response in the artery, we hypothesized that the appearance of contractile ETB receptors reflected expression of ETB receptors in smooth muscle cells of the cerebral arteries, where they are not normally present. Indeed, ETB receptors were visualized in the smooth muscle cell layer of occluded MCA segments using immunohistochemistry, confocal microscopy, and colocalization of the receptors with the smooth muscle cell marker β-actin (Figure 1) (Henriksson et al, 2007a; Maddahi and Edvinsson, 2008). Interestingly, permanent MCAO did not result in ETB upregulation in the occluded MCA (unpublished data). This suggests that ETB upregulation is a metabolically active process, involving de novo gene transcription and protein synthesis, which cannot take place under chronic ischemic conditions.

Figure 1
Immunofluorescence staining for 5-hydroxytryptamine type 1B (5-HT1B), angiotensin type 1 (AT1), and endothelin type B (ETB) receptors in the ischemic middle cerebral artery (MCA), cerebral microvessels (Mic.V), and surrounding brain tissue (brain). There ...

Subsequently, transcriptional upregulation of vascular ETB receptors after MCAO has been confirmed in several studies (Henriksson et al, 2007a, 2007b). In one study, the authors reported a slight but significant increase also in ETA receptor-mediated contraction of occluded MCAs when compared with contralateral MCAs and ipsilateral MCAs from sham-operated rats (Henriksson et al, 2007a). This difference was not seen in other studies (Henriksson et al, 2007a; Stenman et al, 2002, 2007) and may reflect a relatively small ETA receptor upregulation much less pronounced than in the case of the ETB receptor.

Most recently, we studied changes in ETB receptor expression in the Tamura model of distal MCAO (Tamura et al, 1981a, 1981b), where the main MCA branch is occluded permanently at a point distal from the Circle of Willis, after narrowing and branching of the MCA. In this model, the area supplied by the occluded MCA is much smaller with better possibilities for collateral perfusion of the occluded area. Laser Doppler studies confirmed that, at least in our hands, there is not complete ischemia of the distal MCA region (unpublished data). In this model, ETB receptor upregulation in the occluded MCA was demonstrated when the MCA was both occluded permanently with a suture (Rasmussen et al, 2011) or transiently (Kristiansen et al, 2011) using a microsurgical hook (Bonfils et al, 2006). This work revealed two interesting aspects: (1) ETB receptors were upregulated distal to the occlusion but not proximally (Rasmussen et al, 2011), suggesting that loss of tension in the vascular wall is a key phenomenon in initiating receptor upregulation and (2) upregulation of ETB-mediated vasoconstrictive responses was evident after only 1 hour of reperfusion following a 2-hour MCAO, whereas no increase in smooth muscle ETB receptor protein levels could be detected at this time point by immunohistochemistry (Kristiansen et al, 2011). This suggests that there may be a rapid early phase of functional ETB receptor upregulation and a later phase with stronger upregulation, involving de novo synthesis of ETB receptors (Kristiansen et al, 2011).

Several other studies point to a major role for the endothelin system in the pathophysiology of ischemic stroke. For instance, it has been suggested that increased endothelin-induced contractility after cerebral ischemia leads to decreased perfusion of the ischemic area and subsequently an enlargement of the ischemic core (Asano et al, 1989; Robinson et al, 1990). In addition, exogenous ET-1 is able to decrease CBF to levels that induce ischemia (Macrae et al, 1993). After both ischemic stroke and SAH, the levels of ET-1 are increased in plasma, cerebrospinal fluid, and cerebral tissue (Lampl et al, 1997; Neuschmelting et al, 2009; Thampatty et al, 2011; Viossat et al, 1993), and although the detected levels are lower than the ones necessary to cause vasoconstriction under normal conditions, increased ET-1 sensitivity of cerebral arteries due to receptor upregulation may allow secreted ET-1 to cause detrimental cerebral vasoconstriction. However, attempts to treat ischemic stroke with specific ET receptor antagonists have produced conflicting results. Selective ETA receptor antagonists increase cerebral perfusion and decrease the ischemic area in some studies (Dawson et al, 1999; Patel et al, 1996) but not others (Bhardwaj et al, 2000; Umemura et al, 1995). Similarly, the ETA/ETB receptor antagonist Bosentan gives varying results when used in animal models of ischemia (Li et al, 1995; McAuley et al, 1996; Patel and McCulloch, 1996). Furthermore, an ETB receptor antagonist, BQ788, actually exacerbated ischemic damage (Chuquet et al, 2002), possibly due to blockade of endothelial-dependent ETB receptor-mediated vasodilatation.

Upregulation of cerebrovascular receptors during ischemic stroke also occurs in the angiotensin system. A somewhat delayed increase in angiotensin AT1 receptors was observed in the rat transient MCAO model (Stenman and Edvinsson, 2004; Stenman et al, 2007). This was evident by significantly stronger contractile responses to angiotensin II in the MCA 48 hours after the occlusion. The effects were blocked by the AT1 receptor inhibitors candesartan or losartan but not by the AT2 receptor inhibitor PD123319. Furthermore, AT1 receptor protein levels are increased in the occluded MCA (Figure 1) (Maddahi and Edvinsson, 2008). Interestingly, the authors also demonstrated increased levels of angiotensin converting enzyme mRNA in the occluded MCA, indicating that the level of angiotensin II production may be increased in the vessel wall, which would further exacerbate the vasoconstrictive angiotensin II signaling axis. Also in the Tamura model of permanent distal MCAO, at 48 hours after the occlusion, AT1-mediated contractile responses were upregulated in the occluded MCA in segments distal to the point of occlusion, not proximally (Rasmussen et al, 2011). Several clinical and experimental studies point toward important roles for the angiotensin system in the pathophysiology of ischemic stroke. Infusion of angiotensin II impairs a favorable outcome after cerebral ischemia (Hosomi et al, 1999), and blockade of angiotensin AT1 receptors in the acute experimental ischemic stroke is beneficial (Engelhorn et al, 2004; Hosomi et al, 2005). Clinically, favorable effects of AT1 receptor blockade in acute ischemic stroke were observed in the Acute Candesartan Cilexetil in Stroke Survivors (ACCESS) study, which showed that treatment with an AT1 receptor blocker during 7 days after the onset of ischemic stroke improved cardiovascular morbidity and mortality during the following 12 months (Schrader et al, 2003).

A third type of vasoconstrictor receptors, 5-hydroxytryptamine (5-HT) receptor subtype 5-HT1B, is also upregulated in the MCA after focal ischemic stroke (Figure 1) (Maddahi and Edvinsson, 2008). Increased levels of 5-HT1B receptors were demonstrated in the smooth muscle layer of occluded (2 hours) and reperfused MCAs. Later, 5-HT1B receptor upregulation was demonstrated in the Tamura MCAO model in MCA segments distal to the occlusion (Rasmussen et al, 2011). Together, these findings indicate that phenotypic receptor changes after focal ischemic stroke are not limited to a specific receptor type, but perhaps indicate that ischemic arteries undergo a more generalized change in their vasoconstrictor receptor expression profile.

A key mechanistic question is if the described receptor upregulation events are limited to the large cerebral arteries or if microvessels in the affected brain area are similarly affected. This was addressed in a recent study using the proximal 2 hours MCAO model (Maddahi and Edvinsson, 2008). By means of immunohistochemistry, confocal microscopy, and Western blots, it was demonstrated that microvessels within the ischemic area also overexpress ETB, 5-HT1B, and AT1 receptors compared with microvessels in sham-operated rats (Maddahi and Edvinsson, 2008) (Figure 1).

In the above-described studies, occlusion of a cerebral artery gives rise to a local vasoconstrictor receptor upregulation in the occluded artery only distal to the point of occlusion. This raises the question whether similar receptor changes may be found in stroke types, where the blood supply to a larger part of the brain is transiently disrupted by an extracranial cause, such as carotid artery thrombosis. In the human brain, carotid artery stenosis or occlusion leads to a focal forebrain ischemia which, depending on the collateral supply, can range from no infarct to partial middle/anterior cerebral artery infarct to malignant hemispheric infarction. This can be modeled in that rat by transient occlusion of both common carotid arteries and concomitant lowering of the systemic blood pressure by hypovolemia (reversible withdrawal of blood from the jugular vein). This causes cerebral ischemia mainly in the forebrain, whereas the posterior brain parts supplied by the vertebral arteries appears almost unaffected by the insult (Smith et al, 1984). In this model, significant upregulation of contractile ETB and 5-HT1B receptors in cerebral artery smooth muscles was recently demonstrated after 15 minutes carotid occlusion and hypovolemia followed by 48 hours of reperfusion (Johansson et al, 2011). Other receptor subtypes, such as the ETA and 5-HT2A receptors, were unchanged by the ischemia. Interestingly, the receptor changes were most pronounced in the anterior cerebral arteries, less pronounced in the MCA, and did not occur in the basilar artery. The anterior cerebral arteries are also the arteries in which the blood flow drops the most during the occlusion and hypovolemia, and they supply the brain area where ischemic brain damage is found. The striking similarity in the receptor changes observed after focal cerebral ischemia induced by intracranial MCAO and this forebrain ischemia model indicates that these changes represents a general vascular response to transient disturbances in blood flow in cerebral arteries.

Subarachnoid Hemorrhage

Similar to ischemic stroke, vascular contractile receptors increased after SAH. Using an experimental model of SAH in rats originally developed by Prunell et al (2002), it was demonstrated that after the SAH, ETB receptors appear on cerebrovascular smooth muscle cells and mediate vasoconstriction (Hansen-Schwartz et al, 2003b). The ETB receptor upregulation was demonstrated by functional contractility studies, immunohistochemistry, Western blotting, and real-time polymerase chain reaction, the latter indicating that the receptor upregulation occurs at the transcriptional level. The ETB receptor upregulation has been demonstrated in both basilar arteries and MCA, reflecting the global nature of the cerebral ischemia associated with SAH. Although cerebrovascular ETB receptor upregulation observed after SAH corresponds well with our findings in the ischemic stroke models, the functional manifestations of the increased number of smooth muscle ETB receptors appear more complex. The upregulated ETB receptors show no response to S6c but a potentiated response to ET-1, which could be antagonized by both an ETB antagonist and an ETA antagonist (Hansen-Schwartz et al, 2002a, 2003b). This may indicate that after SAH, the new smooth muscle ETB receptors exert constriction only in conjunction with smooth muscle ETA receptors (Hansen-Schwartz et al, 2003b) either via direct interactions in homodimers or heterodimers, which have been reported in other systems, or via indirect functional interactions between the two receptor subtypes (Evans and Walker, 2008; Harada et al, 2002).

In studies using a rat double hemorrhage model of SAH, a similar leftwards shift of the ET-1 dose–contraction curve was observed in cerebral arteries from SAH rats compared with sham rats (Konczalla et al, 2006; Vatter et al, 2007a). However, no change was detected in the immunoreactivity for ETB receptors in cerebral arteries after SAH (Vatter et al, 2007b), in contrast with the above findings in the Prunell SAH model. The most likely explanation for these contrasting findings is the different methodologies used for inducing experimental SAH. In the double hemorrhage model, blood is injected into the cisterna magna with low pressure. This injection is repeated after 48 hours; and 3 to 5 days after the second blood injection, CVS develops. In the Prunell model, a single injection of blood into the prechiasmatic subarachnoid space is made at a pressure equal to the mean arterial blood pressure, thus mimicking bleeding from an artery. This gives rise to CVS and delayed cerebral ischemia ~48 hours after the blood injection (see Figure 2). A study performed to clarify the critical events in initiation of the vasoconstrictor receptor changes in the Prunell model (Ansar and Edvinsson, 2009) showed that injection of saline into the prechiasmatic cistern with a pressure equal to mean arterial blood pressure caused significant cerebrovascular ETB upregulation, whereas saline injections at low pressure caused no changes in ETB expression. This suggests that the intracranial pressure increase itself and the resulting acute drop in CBF in this model is sufficient to cause cerebrovascular ETB upregulation. However, high-pressure injections of blood yielded more pronounced ETB upregulation, indicating that the presence of subarachnoid blood also contributes to the receptor upregulation (Ansar and Edvinsson, 2009). On this basis, the lack of acute rise in intracranial pressure may be the reason for the lack of cerebrovascular ETB upregulation in the rat double hemorrhage model.

Figure 2
Time course of changes in cerebral blood flow following subarachnoid hemorrhage (SAH) in humans and in the rat prechiasmatic injection SAH model. (A) Schematic prediction of the typical biphasic nature of the cerebral ischemia associated with SAH in humans ...

As is the case in ischemic stroke models, cerebrovascular receptor changes after SAH are not limited to endothelin receptors but also includes 5-HT1B (Hansen-Schwartz et al, 2003a) and AT1 (Ansar et al, 2008) receptors. Furthermore, a recent study demonstrated SAH-induced upregulation of thromboxane A2 receptors (Ansar et al, 2010). However, not all contractile receptors change in experimental SAH as other amine and neuropeptide receptors, contractile as well as relaxant, are unaffected (Ansar, unpublished data). Most interestingly, the time course of upregulation of the ETB, 5-HT1B, and AT1 receptors was demonstrated to correlate with the time course of delayed cerebral ischemia, suggesting an important pathophysiological role for upregulated vasoconstrictor receptors (Ansar et al, 2008).

In summary, a number of vasoconstrictor GPCRs expressed in cerebral arteries show expressional plasticity in both hemorrhagic and ischemic stroke models, indicating that this may be a common response of the cerebral vasculature leading to increased vasoconstriction after ischemic insults.

Organ Culture as a Method to Investigate Cerebrovascular Receptor Changes

The first evidence that cerebral arteries can undergo dynamic changes in endothelin receptor expression came from rat basilar arteries and MCAs placed in organ culture for 1 to 2 days (Hansen-Schwartz and Edvinsson, 2000; Leseth et al, 1999). This treatment caused a leftwards shift of the dose–response curves for ET-1 (indicating increased sensitivity to ET-1) and the appearance of a strong ETB-specific contractile response to S6c (Hansen-Schwartz et al, 2002a; Nilsson et al, 1997). The time course of endothelin receptor changes in cultured MCAs is relatively fast, with a small contractile response to S6c after just 6 hours of organ culture (Henriksson et al, 2003; Kristiansen et al, 2011). After 24 or 48 hours of culture, there is a strong S6c response accompanied by a leftwards shift of the ET-1 concentration–contraction curve (Hansen-Schwartz et al, 2002b; Henriksson et al, 2003). After 24 hours of organ culture, ETB mRNA and protein levels in the smooth muscle layer are increased compared with fresh vessels, while ETA mRNA and protein levels remain unchanged (Henriksson et al, 2003). Moreover, both the transcriptional inhibitor actinomycin D and the translational inhibitor cycloheximide abrogate the ETB receptor upregulation during organ culture, underscoring the dependence of the protein on de novo gene transcription and protein synthesis (Henriksson et al, 2003). Organ culture also causes an increased contractile response to 5-carboxamidotryptamine (5-CT) due to transcriptional upregulation of the 5-HT1B receptor subtype (Hoel et al, 2001).

Since changes in vasoconstrictor responses after in vitro organ culture show a striking similarity to the changes observed in animal models of ischemic and hemorrhagic stroke, organ culture can be used as a convenient in vitro method to study the pharmacological characteristics, time course, and underlying cellular and molecular mechanisms of cerebrovascular receptor alterations.

Cerebrovascular Receptor Changes in Human Arteries

Because of the clinical relevance, it is important to know if human cerebral arteries show the same GPCR expression profiles as found in rats, and if they display a similar degree of receptor plasticity with cerebral ischemia and in vitro organ culture. To address the first part of this question, small samples of cortex arterioles were obtained in conjunction with neurosurgical tumor resections or operations to remove epileptic seizure areas. These vessels indeed express ETA and ETB receptors (Nilsson et al, 1997), AT1 (Ahnstedt et al, 2011; Ansar et al, 2009), 5-HT1B (Nilsson et al, 1999), and thromboxane A2 (Uski et al, 1983) receptors. Moreover, freshly obtained human cerebral arteries exhibit ET-1-induced responses that were found to be similar to the responses observed in fresh rat cerebral arteries; ET-1 elicited an ETA receptor-mediated contraction with Emax 112% and pEC50 9.2, whereas S6c elicited an ETB receptor-mediated dilatation on precontraction (Nilsson et al, 1997).

To investigate receptor plasticity in human cerebral arteries, the in vitro organ culture method has been used. However, in cultured human cortical cerebral arteries, the picture was somewhat different compared with cultured rat cerebral arteries; organ culture of human arteries enhanced the response to ET-1 in terms of both sensitivity and potency, Emax 152% and pEC50 10.3 (Hansen-Schwartz et al, 2002a). The ET-1-induced contraction was solely ETA receptor dependent. In contrast, S6c did not elicit any contraction (Hansen-Schwartz et al, 2002a). Furthermore, contractile responses mediated by AT1 and 5-HT1B receptors were also found to be increased in human cerebral arteries on organ culture, and the upregulation of ETB, 5-HT1B, and AT1 receptors in the smooth muscle layer was confirmed with immunohistochemistry (Ahnstedt et al, 2011; Ansar et al, 2009). Thus, human cerebral arteries clearly have the ability to modulate their vasoconstrictor receptor expression profile during culture. The changes were similar to those seen in rat cerebral arteries, although the importance of the ETA receptor appears to be greater in human than in rat cerebral arteries, where only the ETB receptor is upregulated on organ culture.

To discuss whether GPCR changes are induced by cerebral ischemia in vivo in humans, a series of studies examined postmortem cerebral artery samples from stroke patients. In the first series of cerebrovascular samples, it was observed that both large vessels and microvessels had more ETA and ETB receptor mRNA as compared with control specimens (Hansen-Schwartz et al, 2002c). A later study compared MCA samples from 10 subjects who had died from a stroke and 10 subjects who died due to a myocardial infarct. Analysis of mRNA expression and the expression and localization of the encoded proteins validated the earlier results on changes in receptor expression for endothelin receptors but also showed enhanced expression of receptors in the smooth muscle cells for AT1 and 5-HT1B (Vikman and Edvinsson, 2006).

Intracellular Signaling Mechanisms Involved in Cerebrovascular Receptor Upregulation

Following discovery and characterization of cerebrovascular receptor changes, an extensive series of studies have been aimed at identifying upstream signal transduction mechanisms and transcription factors involved in the alteration of vascular GPCR gene transcription and protein synthesis in cerebral ischemia (summarized in Table 2).

Table 2
Overview of signal transduction components involved in cerebrovascular receptor changes in various stroke models

Mitogen Activating Protein Kinases

One of the key findings is that mitogen activating protein kinase (MAPK) kinases have an important role in cerebrovascular receptor plasticity. There are three major MAPKs, p38, ERK1/2, and JNK (c-Jun NH2-terminal kinase), each of them located downstream of a dynamic chain of kinases. Each MAPK signaling pathway involves an MAPKKK that can activate MAPKKs, which in turn activate MAPKs. p38 and SAPK/JNK are considered inflammatory MAPKs and tend to be activated by inflammatory cytokines and cellular stress. ERK1/2 is considered mainly mitogenic and has a predominant role in growth factor receptor signaling (Boulton et al, 1991; Grethe et al, 2004; Hsieh and Nguyen, 2005; Kumar et al, 2003). The MAPKs elicit some of their effects through phosphorylation of transcription factors, thus initiating DNA binding and transcriptional regulation. Transcription factor activation is somewhat redundant between the various MAPKs, with the same transcription factor sometimes being activated by two or more MAPKs. There are also transcription-independent effects of MAPK activity such as cytokine mRNA transportation from the nucleus (Karin, 2005), increased translation, and mRNA stability (Clark et al, 2003; Kumar et al, 2003; Saklatvala et al, 2003).

One of our earliest findings was that cytokines, which activate p38 MAPK, are able to increase the ETB receptor-mediated contractions in arteries subjected to organ culture (Uddman et al, 1999). Other studies have shown an involvement of the MEK/ERK1/2 pathway in cerebral ischemia, and inhibitors toward this pathway are able to diminish the ischemic area (Alessandrini et al, 1999; Namura et al, 2001). In addition, Lennmyr et al (2002) demonstrated activation of ERK1/2 in cerebral arteries after MCAO.

On this basis, the involvement of ERK1/2 and p38 MAPK pathways was assessed in the upregulation of contractile ETB receptors in artery culture (Henriksson et al, 2004, 2007a). Inhibitors tested were U0126, which inhibits MEK1/2 (the MAPKK of ERK1/2), SB386023, which inhibits Raf (the MAPKKK of ERK1/2), and SB239063, which inhibits p38. In MCAs cultured in the presence of ERK1/2 pathway inhibitors, the upregulation of ETB receptor-mediated contractile responses was diminished. This was not seen with the p38 inhibitor (Henriksson et al, 2004). Furthermore, U0126 and SB386023 diminished ETB mRNA levels after organ culture, whereas SB386023 and SB239063 showed a tendency to elevate ETA receptor mRNA levels. The difference between the functional ETA responses and the ETA mRNA level could simply be due to the fact that the mRNA level is increased at an earlier stage of the organ culture and is returning to their original values at the 24-hour time point. The raf inhibitor SB386023 also modified expression of ETB receptor protein in smooth muscle cells (Henriksson et al, 2004). In a recent study, a number of MAPK inhibitors were compared for their ability to prevent the upregulation of various cerebrovascular vasoconstrictor receptors during organ culture (Sandhu et al, 2010a). It was found that the MEK/ERK inhibitor U0126 was effective in preventing ETB and 5-HT1B upregulation, while other MAPK inhibitors (PD98059, SL327, AG126) were not. Most interestingly, U0126 and SB386023 were effective in inhibiting vasoconstrictor receptor upregulation even when applied at 6 and 12 hours, respectively, after the start of the incubation (Jamali and Edvinsson, 2006; Sandhu et al, 2010a). These findings suggest the possibility that this treatment could be effective even if given hours after the stroke occurrence.

Several in vivo situation studies using the rat MCAO model have confirmed the role of MEK–ERK1/2 signaling in focal cerebral ischemia. Treatment with U0126, given systemically in mg doses, prevented phosphorylation of ERK1/2 and the downstream transcription factor Elk-1 as well as suppressed upregulation of ETB, 5-HT1B, and AT1 receptors in cerebral arteries and microvessels in the brain area affected by ischemia (Figures 1 and and3).3). Middle cerebral artery occlusion resulted in an infarct of about 25% of the brain volume, as visualized by 2,3,5-triphenyltetrazolium chloride staining. In animals treated with U0126, the ischemic region was reduced to 10% to 15% of the brain volume at 2 days after MCAO, representing a 50% reduction in infarct size (Henriksson et al, 2007a; Maddahi and Edvinsson, 2008). There was also a significantly improved neurologic function of the animals (Henriksson et al, 2007a). Interestingly, the inhibitor exerted equally positive effects whether administered immediately after the MCAO or 6 hours after the insult, which is within the clinically relevant therapeutic time window (Maddahi and Edvinsson, 2008). This area of research has received little attention before; however, Slevin et al (2000) observed in microvessels within the penumbra that ERK1/2 is activated in human brain after acute ischemic stroke. Moreover, ET-1 levels are increased following a stroke and may regulate ERK1/2 in vascular smooth muscle cells (Brehm et al, 2002).

Figure 3
Immunofluorescence staining for phospho-extracellular regulated kinase 1/2 (pERK1/2) and transcription factor phospho-ELK-1 (pELK-1) in the ischemic middle cerebral artery (MCA), cerebral microvessels (Mic.V), and surrounding brain tissue (brain) ...

Functional consequences of MEK/ERK inhibition in stroke have been further substantiated by studies using the rat SAH model. In this model, ERK1/2 was found to be activated in the smooth muscle layer of cerebral arteries within minutes of initiation of the SAH, while other kinases (p38 and SAP/JNK) only appear phosphorylated at 2 days after the SAH (Ansar and Edvinsson, 2008). In an initial in vivo pharmacological study, the specific Raf inhibitor SB386023 was administered via a cisternal catheter before and immediately after the SAH as well as every 12 hours for 2 days after the SAH (Beg et al, 2006). This route of administration is clinically relevant since many hospitalized SAH patients with risk of developing CVSs have an intracranial catheter inserted to monitor and regulate the intracranial pressure. The animals tolerated the treatment well and the inhibitor showed capable of normalizing endothelin, AT1, and 5-HT receptor expression in cerebral vessels in SAH animals. This effect correlated well with the regional CBF and neurology score, which were both compromised in SAH animals and normalized in SAH animals treated with SB386023 (Beg et al, 2006). Perhaps, the most exciting finding was that the Raf blocker could be given up to 6 hours after the SAH with an equally good result. In a subsequent study, the MEK inhibitor U0126 was evaluated for effects on functional outcome after SAH (Larsen et al, 2010). Treatment with U0126 commencing at 6 hours after the SAH was able normalized both vasoconstrictor receptor expression and neurologic function at 2 days after SAH.

Protein Kinase C and Calcium–Calmodulin-Dependent Kinase II

Decades of research has revealed a central role for calcium overload in the cellular responses to neuronal ischemic injury (Siesjo et al, 1995). High levels of intracellular calcium result in the activation of various protein kinases, including protein kinase C (PKC) and calcium–calmodulin-dependent kinase II (CaMKII) (Bright and Mochly-Rosen, 2005; Waxham et al, 1996; Wieloch et al, 1991). In cerebral artery smooth muscle cells, PKC has been implicated in calcium sensitization, mechanotransduction, and myogenic constriction (Baek et al, 2010; Nakayama and Tanaka, 1993) as well as in the pathogenesis of CVSs after SAH (Laher and Zhang, 2001; Roman et al, 2006). Both PKC and CaMKII are also well-known regulators of the smooth muscle contractile machinery (Kim et al, 2008).

Protein kinase C is a family of serine–threonine kinases, which consists of 11 cloned PKC subtypes that all regulate a broad spectrum of cellular functions. The first studies implicating PKC in the mechanisms behind cerebrovascular receptor plasticity demonstrated that PKC is critically involved upstream of the upregulation of ETB receptors after organ culture (Hansen-Schwartz et al, 2002b; Henriksson et al, 2003). A subsequent study examining the involvement of specific PKC subtypes demonstrated expression of a limited number of PKC subtypes (α, γ, δ, and epsilon) (Henriksson et al, 2006). This study also revealed that different PKC inhibitors work differently on ETB receptor contractile function, mRNA, and protein levels. The general PKC inhibitor, Ro-31-8220, attenuated both the contractile ETB receptor-mediated response and the upregulated ETB receptor mRNA levels after organ culture. However, Ro-31-8220 inhibits not only PKC, but also other factors such as c-jun, JNK, and mitogen-activated protein kinase phosphatase-1 (Beltman et al, 1996; Standaert et al, 1999), and thus the effects may not be solely dependent on PKC inhibition. A subsequent study tested inhibitors with different PKC subtype specificity and found that the PKC inhibitors bisindolylmaleimide I, Ro-32-0432, and 20 to 28 (a peptide mimicking an inactivating part of PKC) (Eichholtz et al, 1993) diminished ETB receptor-mediated contractions and ETB protein levels after organ culture while not affecting ETA receptor-mediated contractions (Henriksson et al, 2006). Ro-32-0432 also effectively abolished the increase in ETB mRNA during organ culture (Henriksson et al, 2006).

When Ro-32-0432 was administered in vivo to rats after MCAO and reperfusion, it reduced the infarct volume, improved neurology score, and normalized ETB-mediated vasomotor responses in ipsilateral cerebral arteries (Henriksson et al, 2007b). Furthermore, RO-32-0432 administered intrathecally to rats with experimental SAH attenuated the delayed reduction in CBF and normalized vasomotor responses mediated by ETB and 5-HT1B receptors (Beg et al, 2007). Activation of various PKC isoforms as early as 1 hour after SAH was demonstrated in a quantitative Western blot study (Ansar and Edvinsson, 2008). This study also revealed an interesting interaction between PKC and MEK–ERK1/2 signaling in cerebral arteries after SAH, which is also supported by molecular data from others (Ginnan et al, 2006).

As mentioned above, calcium has a central role in neuronal cell death and in vascular smooth muscle contraction–excitation coupling, but its significance for cerebrovascular vasoconstrictor receptor plasticity is less well understood. The calcium-activated CaMKII is known to have effects on gene regulation, and in a recent study, Waldsee et al (2010) examined the involvement of CaMKII and various calcium channels in endothelin receptor regulation in cerebral arteries on organ culture. The ETB receptor upregulation was attenuated by coincubation with the inositol 1,4,5-triphosphate receptor (IP3R) inhibitor xestospongin C, -type voltage-operated calcium channel inhibitor nifedipine, and the CaMKII inhibitor KN93. KN93 and xestospongin C attenuated, and nifedipine promoted K+, S6c, and ET-1-induced contractions after organ culture, indicating that both ETB receptor upregulation and ETB-independent (K+-induced) contraction involves CaMKII, voltage-operated calcium channels, and IP3 channels (Waldsee et al, 2010).

Upstream Initiators of Cerebrovascular Signal Transduction and Receptor Changes

An important question is ‘What starts the phenotypic receptor changes?' We hypothesize that the change in vascular wall shear stress and luminal pressure that occur during a stroke or organ culture is one important factor (Olesen et al, 1988). An early study of isolated mesenteric arteries were perfused at different flow levels and perfusion pressures (Szok et al, 2001) showed that perfusion at increased pressure (150 mm Hg) results in enhanced ETB receptor mRNA expression (Lindstedt et al, 2009). This study supports the hypothesis that pressure changes can induce receptor changes.

This hypothesis is also supported by in vivo studies (Rasmussen et al, 2011), in which activation of ERK1/2 and upregulation of AT1, 5-HT1B, and ETB receptors was observed distal to a microsuture occlusion of a distal branch of the MCA (Tamura et al, 1981a) but not proximal. Since the same low degree of ischemia and inflammation was present around the MCA both proximally and distally to the knot, it suggests that the crucial initiating factor is the drop in wall tension distally to the knot. However, it is still not clear which mechanosensitive molecular factors that ‘sense' this and how it is conveyed to the intracellular processes that lead to receptor upregulation. Furthermore, it is not clear whether it is the transient drop or the subsequent increase in shear stress during reperfusion, or a combination of the two that are the pivotal factor initiating the receptor changes. The in vitro experiments (Lindstedt et al, 2009) in which increased perfusion pressure induced ETB receptor upregulation points to the reperfusion process as at least a contributing factor. Furthermore, it is possible that the initiation, propagation, and maintenance of the process of vasoconstrictor receptor upregulation involve other factor besides shear stress changes, such as cytokines, oxidative stress, growth factors, and vasoactive hormones.

It has been shown recently that lipid soluble smoke particles can act via MAP kinases and nuclear factor-κB to enhance the ETB receptor upregulation process during organ culture and coincubation with low-density lipoprotein further enhances this process (Sandhu et al, 2010b; Xu et al, 2008, 2010). In addition, ETB receptors are elevated in vascular smooth muscle following experimental chronic increases in intraluminal pressure (Lindstedt et al, 2009) and in human hypertension (Nilsson et al, 2008), which is a well-known risk factor for stroke. Thus, a range of stroke risk factors are able to enhance cerebrovascular vasoconstrictor receptor upregulation, and this mechanism may be a target for therapy to minimize stroke risk in certain patients.

The Role of Inflammation in Cerebrovascular Pathophysiology After Stroke

The reduction in CBF after a stroke results in a robust inflammatory response in the injured brain tissue that exacerbates tissue damage for several days after the insult (Mitsios et al, 2006). This response is characterized by expression of inflammatory genes with local activation and release of several cytokines, chemokines, adhesion molecules, and proteolytic enzymes (Endres et al, 2008). Some of the factors involved after ischemic stroke are tumor necrosis factor-α, interleukin-1β (IL-1β), IL-6, and inducible nitric oxide synthase, which are produced by a variety of activated cell types; endothelial cells, microglia, neurons, platelets, monocytes, macrophages, and fibroblasts (Huang et al, 2006). Furthermore, there is now clinical evidence of an upregulation of IL-6 after SAH (Sarrafzadeh et al, 2011).

Recently, it has become clear that the inflammatory process after stroke not only affects the brain tissue itself but also exerts detrimental effects in the walls of cerebral arteries. After cerebral ischemia, the blood–brain barrier is disrupted, which allows activated leukocytes to infiltrate the smooth muscle layer of cerebral arteries. Interestingly, recent work suggests that there is a strong link between inflammatory processes in cerebrovascular walls and upregulation of vasoconstrictor receptors after stroke. Thus, 2 hours of MCAO followed by reperfusion for 46 hours resulted in enhanced levels of tumor necrosis factor-α, IL-1β, IL-6, and nitric oxide synthase in the smooth muscle layer of the ischemic MCA and in associated intracerebral microvessels (Maddahi and Edvinsson, 2010). In experimental SAH, the delayed global cerebral ischemia 2 days after the SAH was also shown to be associated with enhanced protein levels of IL-1β, IL-6, and nitric oxide synthase in the smooth muscle layer of cerebral arteries (Maddahi et al, 2011). Blockage of the MEK/ERK pathway prevented this response in both models, and this effect could also be seen when treatment with the blocker was delayed for up to 6 hours after the insult (Maddahi and Edvinsson, 2010; Maddahi et al, 2011).

In both the MCAO and SAH models, costaining with smooth muscle marker β-actin showed that the upregulated cytokines were localized to the smooth muscle layer of the cerebral arteries and microvessels and detailed morphological analyses using confocal microscopy revealed only negligible amounts in the surrounding adventitia and brain parenchyma (Maddahi and Edvinsson, 2010; Maddahi et al, 2011). However, the authors did not find increased cytokine mRNA levels in the cerebral artery walls after SAH (Maddahi et al, 2011). This suggests that the cytokines in the smooth muscle layer are either synthesized outside the vessels or by a small subpopulation of infiltrating cells in the smooth muscle cell layer, such as leukocytes.

The formation of edema and opening of the BBB in cerebral ischemia is associated with enhanced expression of metalloproteinase-9 (MMP-9) and with tissue inhibitor of MMP-1 (TIMP-1) as a counter-regulatory mechanism. In experimental MCAO and SAH, enhanced protein and mRNA expression of MMP-9 and TIMP-1 has been demonstrated in cerebral vessel walls. Interestingly, MMP-9 and TIMP-1 was especially associated with smooth muscle actin but there was no overlap with the astrocyte/glial cell marker GFAP in the vessel walls, indicating that the transcriptional upregulation takes place in the vascular smooth muscle cells themselves (Maddahi et al, 2009, 2011). Treatment with inhibitors of the MEK–ERK1/2 pathway normalized the expression of MMP-9 and TIMP-1 (Maddahi et al, 2009, 2011), indicating that both upregulation of pro-inflammatory mediators and extracellular-matrix-related proteins is governed by at least some of the same signaling pathways as cerebrovascular receptor upregulation.

Signal Transduction Inhibitors Versus Vasoconstrictor Receptor Antagonists

In appreciation of the potential importance of local vasoconstriction for the development of cerebral ischemic damage after a stroke, several attempts have been made to treat ischemic stroke as well as SAH with receptor antagonists targeted to a specific vasoconstrictor receptor subtype. For example, in ischemic stroke, antagonists of angiotensin receptors (Chrysant, 2007; Hosomi et al, 2005; Lou et al, 2004) and endothelin receptors (Dawson et al, 1999; Edvinsson, 2009) have been tested in experimental models and/or clinical trials. In SAH, some of the first experimental treatments against the delayed vasoconstriction were designed to block specific vascular receptors that were thought to be involved (Wilkins, 1990). This approach is still ongoing today, for example the clazosentan trial program (Macdonald et al, 2008a; Schubert et al, 2008), which showed a reduction in the relative risk of angiographic vasospasm in SAH patients treated with the highest drug dose. However, this treatment failed to show significant reduction in the number of patients exhibiting delayed neurologic deterioration; and, even more disappointingly, there was no beneficial effect on outcome after 3 months of observation after stroke (Macdonald et al, 2008b).

Since a large body of work now points to the combined, synergistic involvement of several vasoconstrictor receptors in vascular pathophysiology after a stroke, a study was performed to evaluate the effect of combined inhibition of the angiotensin and endothelin systems in experimental ischemic stroke (Stenman et al, 2007). AT1 receptor antagonism has been shown to improve outcome after ischemic stroke, and it has been suggested that its beneficial effect is due to increased AT2 receptor stimulation when the AT1 receptor is blocked (Li et al, 2005) or to reduced production of the free radical superoxide, an important mediator of ischemic damage (Sugawara et al, 2005). In the latter combination study neither the AT1 receptor blocker candesartan nor the ETA receptor blocker ZD1611 by themselves significantly affected infarct volume or neurology score (Stenman et al, 2007). However, when candesartan and ZD1611 were administered in combination, the treatment reduced brain damage and improved neurology scores after MCAO, with no effect on mean arterial blood pressure (Stenman et al, 2007). This study clearly underscores the importance of a multitargeted approach in stroke therapy, and highlights the combined action of several vasoconstrictor systems to cause local vasoconstriction and augment brain damage after focal ischemic stroke.

Inhibition of intracellular signaling pathways that govern upregulation of multiple vasoconstrictor receptors in cerebral arteries represents another approach to prevent local vasoconstriction and vascular pathology after stroke. This strategy may prove more efficient and less prone to serious cardiovascular side effects than the combined blockage of various vasoconstrictor receptors. Inhibition of PKC isozyme-specific modulators have been examined and show clinical promise, in particular inhibitors of the δPKC subtype (Bright et al, 2004). However, subsequent clinical trials could not support this hypothesis (O'Collins et al, 2006). We hypothesize that inhibition of the MEK–ERK1/2 pathway is a more promising approach, since this pathway appears to govern upregulation of a whole panel of cerebrovascular vasoconstrictor receptors after stroke as well as induction of vascular wall inflammation and blood–brain barrier breakdown.

Perspectives—Promises for Novel Stroke Treatments

There is an urgent need for new ways to treat cerebral ischemia since current neuroprotective agents have either proven ineffective or produced deleterious side effects. The work discussed in this review highlights the fact that the cerebral arteries participate actively in the response following an episode of cerebral ischemia in humans and rat (for a schematic summary, see Figure 4). The process involves ERK1/2 activation, which in turn activates the transcription of inflammatory and extracellular-matrix-regulating genes as well as genes for specific vasoconstrictor receptors in the smooth muscle of cerebral arteries (Figure 4). Because of the synergistic nature of these processes, which involve several gene groups, a single factor approach to the treatment of cerebral ischemia seems unlikely to be effective since not only vasoconstrictor receptors are involved but also induction of genes involved in inflammation, apoptosis, and blood–brain barrier modulation.

Figure 4
Schematic illustration of the main conclusions and hypotheses described in this review. BBB, blood–brain barrier; CaMKII, calcium–calmodulin-dependent kinase II; ERK1/2, extracellular-regulated kinase ½ GPCR, G-protein-coupled ...

As discussed in this review, several central cell signaling pathways have been identified that are important for vasoconstrictor receptor upregulation and the subsequent local vasoconstriction as well as induction of proinflammatory and extracellular-matrix-related genes. By blocking these signaling components, cerebral infarct volume after ischemic stroke and delayed cerebral ischemia after SAH can be considerably reduced. These findings suggest that modulation of cerebrovascular intracellular signals in the subacute phase after a stroke may be a novel approach to protecting the brain from damage after a stroke.

Notes

The authors declare no conflict of interest.

Footnotes

This study was supported by the Lundbeck Foundation, Denmark, the Research Council (Grant no. 5958) and the Heart-Lung Foundation, Sweden.

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