Matricellular protein thrombospondin-1 in pulmonary hypertension: multiple pathways to disease

Abstract

Matricellular proteins are secreted molecules that have affinities for both extracellular matrix and cell surface receptors. Through interaction with structural proteins and the cells that maintain the matrix these proteins can alter matrix strength. Matricellular proteins exert control on cell activity primarily through engagement of membrane receptors that mediate outside-in signaling. An example of this group is thrombospondin-1 (TSP1), first identified as a component of the secreted product of activated platelets. As a result, TSP1 was initially studied in relation to coagulation, growth factor signaling and angiogenesis. More recently, TSP1 has been found to alter the effects of the gaseous transmitter nitric oxide (NO). This latter capacity has provided motivation to study TSP1 in diseases associated with loss of NO signaling as observed in cardiovascular disease and pulmonary hypertension (PH). PH is characterized by progressive changes in the pulmonary vasculature leading to increased resistance to blood flow and subsequent right heart failure. Studies have linked TSP1 to pre-clinical animal models of PH and more recently to clinical PH. This review will provide analysis of the vascular and non-vascular effects of TSP1 that contribute to PH, the experimental and translational studies that support a role for TSP1 in disease promotion and frame the relevance of these findings to therapeutic strategies.

Biological Pathways of Long-Term Visit-to-Visit Blood Pressure Variability in the American Population: Cardiovascular Health Study and Women’s Health Initiatives

“…Systolic BP ADAMTS18 ABCG1 ADGRB3 ADCY4 APELA ANKFN1 ARHGEF3 ARHGAP22 ATF2 BMP2K BIRC5 C10orf90 CASC15 CCDC85A CCDC103 CHST15 CCDC149 CMIP CCDC7 COX7B2 CDH4 EML6 CLSTN2 FAM155A CRK FUT8 CTNNA2 GABRA4 DIDO1 GLIPR2 DPF3 GRIP2 ENPP2 HDAC9 EYS ITGAL FAM155A KLF15 FERMT2 NEBL FGF14 OPCML FOXP1 PCP4 GAS8 PRKCB IRF2 PRLR KCNN3 PTPRD LBP PTPRT LGALS14 RAB3GAP1 MAD1L1 RELN NAALADL2 SCIN NFATC2 SORBS1 PITPNA SORCS3 PLCL2 STK32B PROKR2 TNIK RORA TRPC4 SELP VEPH1 SLC44A5 XIRP2 TCTE3 TEAD4 TG THSD4 infarction can induce cardiomyocyte regeneration and subsequently improved heart function [26]. e O-glycosylation of TSR domain-containing protein pathways ( Figure 5) includes thrombospondin-1 (TSP1): a family of genes that maintain vascular structure and homeostasis [27,28]. When TSP1 is upregulated, it decreases nitric oxide activity, limits c-AMP signaling, and increases reactive oxygen species, which leads to vasoconstriction and ischemia [28].…”

“…e O-glycosylation of TSR domain-containing protein pathways ( Figure 5) includes thrombospondin-1 (TSP1): a family of genes that maintain vascular structure and homeostasis [27,28]. When TSP1 is upregulated, it decreases nitric oxide activity, limits c-AMP signaling, and increases reactive oxygen species, which leads to vasoconstriction and ischemia [28]. In addition, TSP1 leads to endothelial dysfunction, smooth muscle cell migration, and abnormal fibroblast activity [28].…”

“…When TSP1 is upregulated, it decreases nitric oxide activity, limits c-AMP signaling, and increases reactive oxygen species, which leads to vasoconstriction and ischemia [28]. In addition, TSP1 leads to endothelial dysfunction, smooth muscle cell migration, and abnormal fibroblast activity [28]. When this gene is downregulated, it increases angiogenesis, vasodilation, and blood flow [28].…”

“…In addition, TSP1 leads to endothelial dysfunction, smooth muscle cell migration, and abnormal fibroblast activity [28]. When this gene is downregulated, it increases angiogenesis, vasodilation, and blood flow [28]. Understanding these roles may help derive sound intervention strategies for controlling visit-to-visit blood pressure variability.…”

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

“…TSP1 in pulmonary disease. At the same time, a link between TSP1 and dysregulation of the pulmonary circulation has been proposed (116,212). PH is a rapidly fatal disease that is characterized by loss of NO signaling, increased ROS, pulmonary vascular rarefaction, and remodeling and subsequent right HF.…”