Concise Review: The Endothelial Cell Extracellular Matrix Regulates Tissue Homeostasis and Repair

Abstract

All tissues are surrounded by a mixture of noncellular matrix components, that not only provide physical and mechanical support to cells, but also mediate biochemical signaling between cells. The extracellular matrix (ECM) of endothelial cells, also known as the perivascular matrix, forms an organ specific vascular niche that orchestrates mechano-, growth factor, and angiocrine signaling required for tissue homeostasis and organ repair. This concise review describes how this perivascular ECM functions as a signaling platform and how this knowledge can impact the field of regenerative medicine, for example, when designing artificial matrices or using decellularized scaffolds from organs. Stem Cells Translational Medicine 2019;8:375-382.

Keywords: Angiogenesis; Cell adhesion molecules; Cell interactions; Endothelial cell; Glycosaminoglycan; Induced pluripotent stem cells; Microvasculature; Tissue regeneration.

Figure 1

The endothelial basement membrane, composed of laminin and collagen IV strands which self‐assemble to form an independent network crosslinked by perlecans and nidogen, is bound by the endothelial cell through integrins (right lower panel). The glycocalyx, formed by membrane‐bound proteoglycans (GAGs), is able to sequester growth factors and constitutes a part of the interstitial matrix functioning as a signaling platform. Long polymeric hyaluronan (orange) crosslinks proteoglycans that carry heparan sulfate (gray) and sialated surface proteins (red), together constituting a gel like layer. Abbreviation: EC, endothelial cell.

Figure 2

Matricellular proteins and glycosaminoglycans that contain heparan sulfate bind with growth factors and orchestrate receptor interaction at the endothelial cell membrane. This will elicit growth factor‐induced downstream cellular events such as Akt (protein kinase B) and mTOR signaling, which define endothelial adaptive responses, such as the secretion of angiocrine factors. The transmission of angiocrine factors to neighboring cells again is governed in turn by these same endothelial extracellular matrix components. Abbreviations: EC, endothelial cell; FGFR, fibroblast growth factor receptor; HAS/hyaluronan, hyaluronan acid synthase with it's product hyaluronan; mTOR, mammalian target of rapamycin; TIE2, tyrosine kinase with Immunoglobulin‐like and EGF‐like domains 2; VEGF, vascular endothelial growth factor.

Figure 3

Activated leukocytes, through the release of Cathepsin L can activate heparanase, leading to the degradation of the luminal endothelial surface glycocalyx 43. This allows the leukocyte to engage with endothelial surface adhesion receptors (such as ICAM‐1) and form a podosome that can invade into the subendothelial matrix. The podosome delivers MT‐1 leading to subsequent binding and local activation of MMPs and matrix degradation. The release of matrikines and matricellular proteins such as TSP‐1 from the matrix counter‐regulate matrix degradation through their respective activation of EGF and CD36 receptors on the subendothelial surface. Abbreviations: EGF, epidermal growth factor; ICAM‐1, intracellular adhesion molecule 1; MMPs, matrix metalloproteinases; MT‐1, membrane type I‐metalloproteinase; TSP‐1, thrombospondin‐1.