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J Neurosci. 2017 Aug 9;37(32):7580-7594. doi: 10.1523/JNEUROSCI.0187-17.2017. Epub 2017 Jul 3.

Vascular Pericyte Impairment and Connexin43 Gap Junction Deficit Contribute to Vasomotor Decline in Diabetic Retinopathy.

Author information

1
Department of Ophthalmology, Brain and Mind Research Institute, Weill Cornell Medicine, Burke Medical Research Institute, White Plains, New York 10605.
2
Department of Ophthalmology, Brain and Mind Research Institute, Weill Cornell Medicine, Burke Medical Research Institute, White Plains, New York 10605 bos2005@med.cornell.edu.

Abstract

Adequate blood flow is essential to brain function, and its disruption is an early indicator in diseases, such as stroke and diabetes. However, the mechanisms contributing to this impairment remain unclear. To address this gap, in the diabetic and nondiabetic male mouse retina, we combined an unbiased longitudinal assessment of vasomotor activity along a genetically defined vascular network with pharmacological and immunohistochemical analyses of pericytes, the capillary vasomotor elements. In nondiabetic retina, focal stimulation of a pericyte produced a robust vasomotor response, which propagated along the blood vessel with increasing stimulus. In contrast, the magnitude, dynamic range, a measure of fine vascular diameter control, and propagation of vasomotor response were diminished in diabetic retinas from streptozotocin-treated mice. These functional changes were linked to several mechanisms. We found that density of pericytes and their sensitivity to stimulation were reduced in diabetes. The impaired response propagation from the stimulation site was associated with lower expression of connexin43, a major known gap junction unit in vascular cells. Indeed, selective block of gap junctions significantly reduced propagation but not initiation of vasomotor response in the nondiabetic retina. Our data establish the mechanisms for fine local regulation of capillary diameter by pericytes and a role for gap junctions in vascular network interactions. We show how disruption of this balance contributes to impaired vasomotor control in diabetes.SIGNIFICANCE STATEMENT Identification of mechanisms governing capillary blood flow in the CNS and how they are altered in disease provides novel insight into early states of neurological dysfunction. Here, we present physiological and anatomical evidence that both intact pericyte function as well as gap junction-mediated signaling across the vascular network are essential for proper capillary diameter control and vasomotor function. Changes to capillary blood flow precede other anatomical and functional hallmarks of diabetes establishing a significant window for prevention and treatment.

KEYWORDS:

connexin43; diabetes; diabetic retinopathy; functional hyperemia; pericyte

PMID:
28674171
PMCID:
PMC5551058
DOI:
10.1523/JNEUROSCI.0187-17.2017
[Indexed for MEDLINE]
Free PMC Article

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