Endothelial Cell Behavior Is Determined by Receptor Clustering Induced by Thrombospondin-1

Abstract

The thrombospondins (TSPs) are a family of multimeric extracellular matrix proteins that dynamically regulate cellular behavior and response to stimuli. In so doing, the TSPs directly and indirectly affect biological processes such as embryonic development, wound healing, immune response, angiogenesis, and cancer progression. Many of the direct effects of Thrombospondin 1 (TSP-1) result from the engagement of a wide range of cell surface receptors including syndecans, low density lipoprotein receptor-related protein 1 (LRP1), CD36, integrins, and CD47. Different or even opposing outcomes of TSP-1 actions in certain pathologic contexts may occur, depending on the structural/functional domain involved. To expedite response to external stimuli, these receptors, along with vascular endothelial growth factor receptor 2 (VEGFR2) and Src family kinases, are present in specific membrane microdomains, such as lipid rafts or tetraspanin-enriched microdomains. The molecular organization of these membrane microdomains and their constituents is modulated by TSP-1. In this review, we will describe how the presence of TSP-1 at the plasma membrane affects endothelial cell signal transduction and angiogenesis.

Deciphering Cell-Cell Communication in Abdominal Aortic Aneurysm From Single-Cell RNA Transcriptomic Data

“…These controversial findings may highlight the cell type specificity of TSP1 functions in aneurysmal disease. TSP1 binds to a wide range of receptors including syndecans, CD36, integrins, and CD47 (23,24), but the role of these ligand-receptor pairs in AAA has not been investigated.…”

Sex-specific differences in atherosclerosis, thrombospondin-1, and smooth muscle cell differentiation in metabolic syndrome versus non-metabolic syndrome mice

“…TSP-1 is a multifunctional protein with cell- and tissue-specific effects, attributed to its differential interaction with and regulation of several cell-surface receptors and matrix-binding partners, in turn modulating cell-cell and cell-matrix interactions ( 41 ). Accumulating literature indicates that TSP-1 signaling via differential receptor activation (CD36, CD47) regulates the function of different vascular cell types, triggering inflammatory cell adhesion and transmigration through the vascular endothelium, LDL pinocytosis by macrophages and foam cell formation, endothelial cell (EC) dysfunction and EC senescence ( 17 , 42 , 43 ). In a healthy vessel, TSP-1 expression is typically low; however, in response to proatherogenic insults such as hyperglycemia and obesity, TSP-1 expression is significantly augmented.…”

“…Moreover, atherosclerotic lesion formation correlated with augmented TSP-1 expression in the vascular 3, 4); however, lanes were re-arranged to improve the clarity of presentation. (17,42,43). In a healthy vessel, TSP-1 expression is typically low; however, in response to proatherogenic insults such as hyperglycemia and obesity, TSP-1 expression is significantly augmented.…”

Thrombospondin-1 Signaling Through the Calreticulin/LDL Receptor Related Protein 1 Axis: Functions and Possible Roles in Glaucoma

“…TSP-1 has many biologic functions, including regulation of cell adhesion and motility, platelet aggregation, cell death, protease activity, ECM organization, and growth factor regulation. Given this multiplicity of functions, TSP-1 has diverse roles in regulation of angiogenesis, inhibition of nitric oxide signaling, endothelial cell barrier function, inflammation/immunity, endoplasmic reticulum stress, fibrosis, and latent TGF-β activation (Adams and Lawler, 2004;Sweetwyne and Murphy-Ullrich, 2012;Murphy-Ullrich and Suto, 2018;Murphy-Ullrich, 2019;Forbes et al, 2021;Kale et al, 2021;Kaur et al, 2021;Morandi et al, 2021). The reader is referred to several excellent reviews covering broader roles of TSP-1 and other matricellular proteins in glaucoma and in fibrotic ECM remodeling for a more extensive discussion (Rhee et al, 2009;Chatterjee et al, 2014;Wallace et al, 2014;Murphy-Ullrich and Downs, 2015;Murphy-Ullrich, 2019;Keller and Peters, 2022).…”