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.