Endothelial Hyaluronan Synthase 3 Augments Postischemic Arteriogenesis Through CD44/eNOS Signaling

Objective: The dominant driver of arteriogenesis is elevated shear stress sensed by the endothelial glycocalyx thereby promoting arterial outward remodeling. Hyaluronan, a critical component glycocalyx, synthesized 3 HAS isoenzymes (hyaluronan synthases 1-3) at plasma membrane. Considering further importance HAS3 for smooth muscle cell and immune functions we aimed to evaluate its role in collateral artery growth. Approach Results: Male Has3 -deficient ( -KO) mice were subjected hindlimb ischemia. Blood perfusion was monitored laser Doppler imaging function assessed measurement flow-mediated dilation vivo. Collateral remodeling high resolution magnetic resonance angiography. A neutralizing antibody against CD44 (clone KM201) injected intraperitoneally analyze hyaluronan signaling After ischemia, -KO showed reduced arteriogenic response with decreased impaired recovery. While postischemic leukocyte infiltration unaffected, diminished pointed towards an function. Indeed, AKT (protein kinase B)-dependent eNOS (endothelial nitric oxide synthase) phosphorylation Ser1177 substantially thigh muscles. Endothelial-specific mimicked ischemia-induced phenotype recovery as observed global -deficiency. Mechanistically, blocking selectively binding site dilation, suggesting through underlying pathway. Conclusions: In summary, contributes ischemia hyaluronan/CD44-mediated stimulation Ser1177. Thus, strategies augmenting or could be envisioned enhance vascularization under pathological conditions.