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Feng, Shuang; Bowden, Neil; Fragiadaki, Maria; Souilhol, Celine; Hsiao, Sarah; Mahmoud, Marwa; Allen, Scott; Pirri, Daniela; Ayllon, Blanca Tardajos; Akhtar, Shamima; Thompson, A. A. Roger; Jo, Hanjoong; Weber, Christian; Ridger, Victoria; Schober, Andreas and Evans, Paul C. (2017): Mechanical Activation of Hypoxia-Inducible Factor 1 alpha Drives Endothelial Dysfunction at Atheroprone Sites. In: Arteriosclerosis thrombosis and Vascular Biology, Vol. 37, No. 11: pp. 2087-2101 [PDF, 3MB]


Objective-Atherosclerosis develops near branches and bends of arteries that are exposed to low shear stress (mechanical drag). These sites are characterized by excessive endothelial cell (EC) proliferation and inflammation that promote lesion initiation. The transcription factor HIF1 alpha (hypoxia-inducible factor 1 alpha) is canonically activated by hypoxia and has a role in plaque neovascularization. We studied the influence of shear stress on HIF1 alpha activation and the contribution of this noncanonical pathway to lesion initiation. Approach and Results-Quantitative polymerase chain reaction and en face staining revealed that HIF1 alpha was expressed preferentially at low shear stress regions of porcine and murine arteries. Low shear stress induced HIF1 alpha in cultured EC in the presence of atmospheric oxygen. The mechanism involves the transcription factor nuclear factor-kappa B that induced HIF1 alpha transcripts and induction of the deubiquitinating enzyme Cezanne that stabilized HIF1 alpha protein. Gene silencing revealed that HIF1 alpha enhanced proliferation and inflammatory activation in EC exposed to low shear stress via induction of glycolysis enzymes. We validated this observation by imposing low shear stress in murine carotid arteries (partial ligation) that upregulated the expression of HIF1 alpha, glycolysis enzymes, and inflammatory genes and enhanced EC proliferation. EC-specific genetic deletion of HIF1 alpha in hypercholesterolemic apolipoprotein E-defecient mice reduced inflammation and endothelial proliferation in partially ligated arteries, indicating that HIF1 alpha drives inflammation and vascular dysfunction at low shear stress regions. Conclusions-Mechanical low shear stress activates HIF1 alpha at atheroprone regions of arteries via nuclear factor-kappa B and Cezanne. HIF1 alpha promotes atherosclerosis initiation at these sites by inducing excessive EC proliferation and inflammation via the induction of glycolysis enzymes.

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