The role of vascular-derived perlecan in modulating cell adhesion, proliferation and growth factor signaling

Abstract

Smooth muscle cell proliferation can be inhibited by heparan sulfate proteoglycans whereas the removal or digestion of heparan sulfate from perlecan promotes their proliferation. In this study we characterized the glycosaminoglycan side chains of perlecan isolated from either primary human coronary artery smooth muscle or endothelial cells and determined their roles in mediating cell adhesion and proliferation, and in fibroblast growth factor (FGF) binding and signaling. Smooth muscle cell perlecan was decorated with both heparan sulfate and chondroitin sulfate, whereas endothelial perlecan contained exclusively heparan sulfate chains. Smooth muscle cells bound to the protein core of perlecan only when the glycosaminoglycans were removed, and this binding involved a novel site in domain III as well as domain V/endorepellin and the α2β1 integrin. In contrast, endothelial cells adhered to the protein core of perlecan in the presence of glycosaminoglycans. Smooth muscle cell perlecan bound both FGF1 and FGF2 via its heparan sulfate chains and promoted the signaling of FGF2 but not FGF1. Also endothelial cell perlecan bound both FGF1 and FGF2 via its heparan sulfate chains, but in contrast, promoted the signaling of both growth factors. Based on this differential bioactivity, we propose that perlecan synthesized by smooth muscle cells differs from that synthesized by endothelial cells by possessing different signaling capabilities, primarily, but not exclusively, due to a differential glycanation. The end result is a differential modulation of cell adhesion, proliferation and growth factor signaling in these two key cellular constituents of blood vessels.

The CS Sulfation Motifs 4C3, 7D4, 3B3[−]; and Perlecan Identify Stem Cell Populations and Their Niches, Activated Progenitor Cells and Transitional Areas of Tissue Development in the Fetal Human Elbow

“…Perlecan modulates stem cell-ECM attachment and may modulate stem cell-integrin and stem cell-cadherin family or other cell receptor interactions such as VEGF2 [76] to influence stem cell survival, differentiation, and proliferation [70,76,77]. Extrinsic interactions with soluble growth factors such as FGF2 may also promote stem cell survival [68,69] through the Wnt signaling pathways [77].…”

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

“…It is knowledgeable that adhesion, proliferation [53][54][55] , migration [56] and autophagy [57,58] are the characteristics of cells [59][60][61] . [61] .…”

Endorepellin-evoked Autophagy Contributes to Angiostasis

“…It is encoded by an ϳ115-kb gene, HSPG2 (4,5), and is expressed in a variety of tissues, both vascular and avascular (6,7). The biological functions of perlecan span a range of processes, including cell adhesion (8,9), endocytosis (10), bone and cartilage formation (11,12), inflammation and wound healing (13,14), thrombosis (15), lipid metabolism (16), autophagy (17), tumor angiogenesis and invasiveness (18 -23), and cardiovascular development (24), where its angiogenic properties are among the most interesting. Perlecan transcription is also induced by TGF-␤ (25) and is rapidly repressed by interferon ␥ (26).…”

“…Perlecan sequesters VEGFA and FGFs via its N-terminal heparan sulfate side chains, which are then released by heparanases and subsequently bind to their cognate receptors, resulting in the induction of angiogenesis (9,28,29). In addition, there is a feedforward loop in that VEGFA induces perlecan synthesis via the activation of VEGFR2, leading to increased angiogenesis (30,31).…”