Thrombospondin-1 and CD47 regulation of cardiac, pulmonary and vascular responses in health and disease

Abstract

Cardiovascular homeostasis and health is maintained through the balanced interactions of cardiac generated blood flow and cross-talk between the cellular components that comprise blood vessels. Central to this cross-talk is endothelial generated nitric oxide (NO) that stimulates relaxation of the contractile vascular smooth muscle (VSMC) layer of blood vessels. In cardiovascular disease this balanced interaction is disrupted and NO signaling is lost. Work over the last several years indicates that regulation of NO is much more complex than previously believed. It is now apparent that the secreted protein thrombospondin-1 (TSP1), that is upregulated in cardiovascular disease and animal models of the same, on activating cell surface receptor CD47, redundantly inhibits NO production and NO signaling. This inhibitory event has implications for baseline and disease-related responses mediated by NO. Further work has identified that TSP1-CD47 signaling stimulates enzymatic reactive oxygen species (ROS) production to further limit blood flow and promote vascular disease. Herein consideration is given to the most recent discoveries in this regard which identify the TSP1-CD47 axis as a major proximate governor of cardiovascular health.

Keywords: Blood flow; CD47; Cardiovascular disease; Nitric oxide; ROS; Thrombospondin-1.

Figure 1. Nitric oxide (NO) signaling within arteries targets multiple cells types to promote blood flow

Endothelial nitric oxide synthase (eNOS) reacts to hormones, including VEGF, and to the mechanical signal of laminar blood flow to increases production of the reactive nitrogen species NO. As a biogas, NO rapidly crosses cell membranes to activate the intracellular target soluble guanylyl cyclase (sGC) stimulating increased production of cyclic guanosine monophosphate (cGMP) itself a signaling intermediate. NO stimulates endothelial cell angiogenesis and suppresses expression of adhesion proteins on cell membranes. NO also acts distal to the site of production. In the artery lumen, NO decreases production of inflammatory cell cytokines and suppresses integrin signaling and platelet aggregation. In the wall of arteries NO acutely inhibits vascular smooth muscle cell contraction to dilate blood vessels and chronically suppresses cell overgrowth and hypertrophy, thus preserving vascular diameter and blood flow.

Figure 2. TSP1 binds and activates cell receptor CD47 to limit blood flow directly and indirectly

Stationary and circulating vascular cells express CD47. TSP1 at picomolar concentrations binds and activates CD47. In endothelial cells this signal alters calcium flux to limit eNOS activation and NO production. On the endothelial cell surface CD47 also constitutively associates with the VEGF receptor (VEGFR2). Soluble TSP1 on binding to CD47 alters this interaction, inhibits VEGF signaling and thus blocks the NO-mediated and NO-independent effects of VEGF. In other cells, including VSMC and platelets activated CD47 directly inhibits the cytoplasmic NO-target sGC and the downstream signal transducer cGMP-dependent kinases (PKG). TSP1, via CD47, also directly inhibits adenylate cyclase production of second messenger cAMP to alter VSMC growth and promote vasoconstriction. In VSMC TSP1, via CD47, stimulates NAPDH oxidase production of superoxide (O₂^•−). In hypoxic endothelial cells TSP1, via CD47, dysregulates the caveolin-1-eNOS interaction and promotes increased reactive oxygen species (ROS) production. ROS further limits vasodilation by then scavenging NO. Together these direct and indirect processes promote vasoconstriction and decrease blood flow.