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Tytuł:
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Endothelial Hyaluronan Synthase 3 Augments Postischemic Arteriogenesis Through CD44/eNOS Signaling.
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Autorzy:
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Schneckmann R; Institute for Pharmacology and Clinical Pharmacology, Medical Faculty (R.S., T.S., C.H., C.L., T.F., J.W.F., M.G.), University Clinics and Heinrich-Heine University Düsseldorf, Germany.
Suvorava T; Institute for Pharmacology and Clinical Pharmacology, Medical Faculty (R.S., T.S., C.H., C.L., T.F., J.W.F., M.G.), University Clinics and Heinrich-Heine University Düsseldorf, Germany.
Hundhausen C; Institute for Pharmacology and Clinical Pharmacology, Medical Faculty (R.S., T.S., C.H., C.L., T.F., J.W.F., M.G.), University Clinics and Heinrich-Heine University Düsseldorf, Germany.
Schuler D; Clinic for Cardiology, Pneumology and Angiology (D.S., M.K.), University Clinics and Heinrich-Heine University Düsseldorf, Germany.
Lorenz C; Institute for Pharmacology and Clinical Pharmacology, Medical Faculty (R.S., T.S., C.H., C.L., T.F., J.W.F., M.G.), University Clinics and Heinrich-Heine University Düsseldorf, Germany.
Freudenberger T; Institute for Pharmacology and Clinical Pharmacology, Medical Faculty (R.S., T.S., C.H., C.L., T.F., J.W.F., M.G.), University Clinics and Heinrich-Heine University Düsseldorf, Germany.
Kelm M; Clinic for Cardiology, Pneumology and Angiology (D.S., M.K.), University Clinics and Heinrich-Heine University Düsseldorf, Germany.; CARID, Cardiovascular Research Institute Düsseldorf, University Hospital Düsseldorf, Heinrich-Heine-University, Germany (M.K., J.W.F.).
Fischer JW; Institute for Pharmacology and Clinical Pharmacology, Medical Faculty (R.S., T.S., C.H., C.L., T.F., J.W.F., M.G.), University Clinics and Heinrich-Heine University Düsseldorf, Germany.; CARID, Cardiovascular Research Institute Düsseldorf, University Hospital Düsseldorf, Heinrich-Heine-University, Germany (M.K., J.W.F.).
Flögel U; Experimental Cardiovascular Imaging, Institute for Molecular Cardiology (U.F.), University Clinics and Heinrich-Heine University Düsseldorf, Germany.
Grandoch M; Institute for Pharmacology and Clinical Pharmacology, Medical Faculty (R.S., T.S., C.H., C.L., T.F., J.W.F., M.G.), University Clinics and Heinrich-Heine University Düsseldorf, Germany.
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Źródło:
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Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2021 Oct; Vol. 41 (10), pp. 2551-2562. Date of Electronic Publication: 2021 Aug 12.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't; Video-Audio Media
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Język:
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English
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Imprint Name(s):
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Publication: 1998- : Baltimore, Md. : Lippincott Williams & Wilkins
Original Publication: Dallas, TX : American Heart Association, c1995-
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MeSH Terms:
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Neovascularization, Physiologic*
Endothelial Cells/*enzymology
Hindlimb/*blood supply
Hyaluronan Receptors/*metabolism
Hyaluronan Synthases/*metabolism
Ischemia/*enzymology
Nitric Oxide Synthase Type III/*metabolism
Animals ; Collateral Circulation ; Disease Models, Animal ; Humans ; Hyaluronan Synthases/genetics ; Ischemia/physiopathology ; Male ; Mice, Inbred C57BL ; Mice, Knockout, ApoE ; Nitric Oxide Synthase Type III/genetics ; Phosphorylation ; Regional Blood Flow ; Signal Transduction ; Time Factors ; Mice
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Contributed Indexing:
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Keywords: arteriogenesis; eNOS; flow-mediated dilation; perfusion
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Substance Nomenclature:
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0 (Cd44 protein, mouse)
0 (Hyaluronan Receptors)
EC 1.14.13.39 (Nitric Oxide Synthase Type III)
EC 1.14.13.39 (Nos3 protein, mouse)
EC 2.4.1.212 (Has3 protein, mouse)
EC 2.4.1.212 (Hyaluronan Synthases)
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Entry Date(s):
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Date Created: 20210812 Date Completed: 20211122 Latest Revision: 20240226
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Update Code:
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20240226
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DOI:
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10.1161/ATVBAHA.121.315478
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PMID:
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34380333
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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.
