Endothelial Hyaluronan Synthase 3 Augments Postischemic Arteriogenesis Through CD44/eNOS Signaling. Issue 10 (12th August 2021)

• Record Type: Journal Article
• Authors: Schneckmann, Rebekka; Suvorava, Tatsiana; Hundhausen, Christian; Schuler, Dominik; Lorenz, Christin; Freudenberger, Till; Kelm, Malte; Fischer, Jens W.; Flögel, Ulrich; Grandoch, Maria
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 41:Issue 10(2021)
• Page Start: 2551
• Page End: 2562
• Publication Date: 2021-08-12
• Subjects: arteriogenesis -- eNOS -- flow-mediated dilation -- perfusion; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.121.315478
• Languages: English
• ISSNs: 1079-5642

Abstract

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