Loss of Endothelial Glycocalyx Hyaluronan Impairs Endothelial Stability and Adaptive Vascular Remodeling After Arterial Ischemia.

Gangqi Wang,Margreet R De Vries,Ton J Rabelink,Anton Jan Van Zonneveld,Wendy M P J Sol,Annemarie M Van Oeveren-Rietdijk,Paul H A Quax,Bernard M Van Den Berg,Hetty C De Boer

doi:10.3390/cells9040824

Abstract

We recently reported that loss of hyaluronan (HA) from the endothelial glycocalyx leads to loss of vessel stability in specific microcirculatory vascular beds. Here we hypothesized that such derangements in the glycocalyx may also impair the adaptive response to vascular ischemia. Endothelial specific conditional hyaluronan synthase 2-KO (Has2-cKO) mice revealed reduced endothelial HA expression and lower hindlimb perfusion at baseline compared to control mice. After a single ligation of the common femoral artery in these mice, we observed dysregulated angiogenesis in the gastrocnemius muscle which did not restore capillary perfusion. Mechanistically, decreased endothelial binding of the pericyte-derived molecule angiopoietin1 (Ang1) could be observed in the Has2-cKO mouse. In vitro angiogenesis assays with an endothelial cell-pericyte coculture confirmed such disturbed Ang1-TIE2 signaling resulting in excessive angiogenesis upon loss of HA. These data could be of relevance to diabetes patients, where we confirm loss of endothelial HA in the microcirculation of muscle tissue, indicating that this may contribute to the known disturbed adaptation to ischemia in these patients. In summary, loss of endothelial HA results in impaired microvascular perfusion and endothelial stability in ischemic gastrocnemius muscle. Endothelial HA is a potential target to improve angiogenic therapy in diabetic patients with critical limb ischemia.

Highlights

IntroductionOne therapeutic strategy that has been explored in this condition is to enhance angiogenesis through administration of growth factors and vasculogenic cells [1]
During peripheral artery disease, occlusion of the arteries can trigger a series of compensatory events, such as arteriogenesis and angiogenesis, to restore perfusion in the ischemic tissue [1,2].One therapeutic strategy that has been explored in this condition is to enhance angiogenesis through administration of growth factors and vasculogenic cells [1]
Muscle sections of critical limb ischemia biopsies of type 2 diabetic patients showed a lower endothelial HA expression co-localizing with CD31 in blood vessels (Figure 5A–C) and, we found increased adipocytes, edema, and myocyte degeneration (Figure 5D), similar to our observations in muscle tissue in Has2-cKO after ligation (Supplementary Figure S4)

Summary

Introduction

One therapeutic strategy that has been explored in this condition is to enhance angiogenesis through administration of growth factors and vasculogenic cells [1]. For vascular homeostasis the selective binding capacity of growth factors and chemokines to endothelial glycocalyx is essential [7,8,9,10]. Like inflammation, hyperglycemia, and atherosclerosis, the endothelial glycocalyx is degraded by enzymes such as heparanase and hyaluronidases [11,12,13]. Such impaired endothelial glycocalyx results in endothelial dysfunction and is associated with a less efficient and defective microvascular perfusion [14,15]

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