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.

Keywords: CD47; Endothelin-1; Nitric  oxide; Nox1; Pulmonary  hypertension; ROS; Thrombospondin-1; Vasorelaxation; cMyc; eNOS.

Figure 1

Thrombospondin-1 negatively intersects vascular NO-ROS. Under healthy conditions TSP1 is almost undetectable. In acute and chronic injury and disease, TSP1 is induced in the systemic vasculature to engage CD47 and limit NO signaling through decreasing eNOS activity, and separately by rendering sGC and PKG resistant to activation. Separately, TSP1 limits cAMP signaling. TSP1 also activates NADPH oxidase 1 (Nox1) increasing superoxide production. Acting via these several pathways TSP1 promotes vascular rarefaction, vasoconstriction and ischaemia.

Figure 2

Thrombospondin-1 in PH. Hypoxia inducible factor-2α (HIF-2α) targets hypoxia response elements (HRE) to increase THSP1 transcription in pulmonary vascular cells. In pulmonary arterial endothelial cells (PAEC) TSP1 via CD47 promotes PH by (1) targeting Cav-1 to dysregulate eNOS while increasing ROS, (2) suppressing cMyc to de-repress ET-1/ETA, and (3) decreasing cell-cell adhesion. TSP1 also increases pulmonary smooth muscle cell (PASMC) migration and fibroblast (PAFIB) activity. In pulmonary arteries, TSP1 inhibits vasorelaxation, increases vasoconstriction and in hypoxia decreases Kv1.5 ion channel effects.