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Hypertension. 2013 Sep;62(3):634-40. doi: 10.1161/HYPERTENSIONAHA.111.00160. Epub 2013 Aug 5.

Hypoxia-inducible factor-1α in vascular smooth muscle regulates blood pressure homeostasis through a peroxisome proliferator-activated receptor-γ-angiotensin II receptor type 1 axis.

Author information

1
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 10 Amistad St, New Haven, CT 06520, USA.

Abstract

Hypertension is a major worldwide health issue for which only a small proportion of cases have a known mechanistic pathogenesis. Of the defined causes, none have been directly linked to heightened vasoconstrictor responsiveness, despite the fact that vasomotor tone in resistance vessels is a fundamental determinant of blood pressure. Here, we reported a previously undescribed role for smooth muscle hypoxia-inducible factor-1α (HIF-1α) in controlling blood pressure homeostasis. The lack of HIF-1α in smooth muscle caused hypertension in vivo and hyperresponsiveness of resistance vessels to angiotensin II stimulation ex vivo. These data correlated with an increased expression of angiotensin II receptor type I in the vasculature. Specifically, we show that HIF-1α, through peroxisome proliferator-activated receptor-γ, reciprocally defined angiotensin II receptor type I levels in the vessel wall. Indeed, pharmacological blockade of angiotensin II receptor type I by telmisartan abolished the hypertensive phenotype in smooth muscle cell-HIF-1α-KO mice. These data revealed a determinant role of a smooth muscle HIF-1α/peroxisome proliferator-activated receptor-γ/angiotensin II receptor type I axis in controlling vasomotor responsiveness and highlighted an important pathway, the alterations of which may be critical in a variety of hypertensive-based clinical settings.

KEYWORDS:

HIF-1α; PPAR-γ; angiotensins; hypertension; muscle, smooth, vascular

PMID:
23918749
PMCID:
PMC4354705
DOI:
10.1161/HYPERTENSIONAHA.111.00160
[Indexed for MEDLINE]
Free PMC Article

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