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

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-1 (HIF-1) in controlling blood pressure homeostasis. The lack of HIF-1 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-1, through peroxisome proliferator-activated receptor-, 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-1-KO mice. These data revealed a determinant role of a smooth muscle HIF-1/peroxisome proliferator-activated receptor-/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.