Regulation of soluble guanylate cyclase by matricellular thrombospondins: implications for blood flow

Abstract

Nitric oxide (NO) maintains cardiovascular health by activating soluble guanylate cyclase (sGC) to increase cellular cGMP levels. Cardiovascular disease is characterized by decreased NO-sGC-cGMP signaling. Pharmacological activators and stimulators of sGC are being actively pursued as therapies for acute heart failure and pulmonary hypertension. Here we review molecular mechanisms that modulate sGC activity while emphasizing a novel biochemical pathway in which binding of the matricellular protein thrombospondin-1 (TSP1) to the cell surface receptor CD47 causes inhibition of sGC. We discuss the therapeutic implications of this pathway for blood flow, tissue perfusion, and cell survival under physiologic and disease conditions.

Keywords: CD47; ROS; cardiovascular disease; cyclic guanosine monophosphate; nitric oxide; soluble guanylate cyclase; thrombospondin-1.

Figure 1

Matricellular TSP1 via CD47 restricts NO-sGC-cGMP signaling. TSP1 inhibits the sGC-cGMP axis via multiple mechanisms to circumvent its beneficial effects. Upstream of sGC-cGMP, TSP1 engages CD47 altering cell calcium flux and VEGF receptor signaling to inhibit eNOS-stimulated NO production. TSP1 via CD36 also inhibits eNOS stimulation in endothelial cells by limiting essential free fatty acid uptake (not pictured). TSP1 through CD47, and SIRP-α, stimulates pathologic superoxide production which catabolizes NO. Increased ROS can be expected to alter adversely key protein residues further inhibiting the sGC-cGMP pathway. At the levels of sGC, TSP1 via CD47 directly inhibits sGC and inhibits its sensitivity to NO and non-NO activation. TSP1 can also stimulate increased calcium flux in certain cells which inhibits sGC activation in T cells. TSP1 via CD47 also inhibits synthesis of H₂S which in turn regulates sGC. Extracellular β-amyloid binds to CD36 and cross talk with CD47 inhibits NO and non-NO activation of sGC. Finally, in vascular smooth muscle cells and platelets TSP1 via CD47 inhibits activation of cGMP-dependent protein kinase.