Category: disease_cascade
PAH is progressive pulmonary vascular remodeling + vasoconstriction → ↑pulmonary vascular resistance → right-ventricular failure. Three endothelial imbalances are the therapeutic targets. (1) NO–sGC–cGMP: endothelial dysfunction lowers nitric oxide → less soluble guanylate cyclase (sGC) activity → less cGMP (a vasodilator second messenger). PDE5 — highly expressed in lung — degrades cGMP, so PDE5 inhibitors (sildenafil, tadalafil) and the direct sGC stimulator riociguat raise cGMP. (2) Endothelin-1: overexpressed in PAH, drives ETA-mediated vasoconstriction + smooth-muscle proliferation → endothelin receptor antagonists (bosentan, macitentan, ambrisentan). (3) Prostacyclin (PGI2): deficient; IP-receptor activation raises cAMP → vasodilation + antiproliferation → prostacyclin analogs (epoprostenol, treprostinil, iloprost) and the IP agonist selexipag. Cross-links: pde5, eta, cyclic-nucleotide signaling.