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.
Organ Systems
respiratory
cardiovascular
Pathway Steps
endothelial-dysfunction → reduced-NO-cGMP — via ↓eNOS → ↓NO → ↓sGC activity → ↓cGMP. Pulmonary endothelial dysfunction lowers nitric oxide, reducing soluble guanylate cyclase activity and the vasodilator cGMP — promoting pulmonary vasoconstriction and remodeling.
cGMP → pulmonary-vasodilation — via PKG → ↓cytosolic Ca²⁺ → ASM relaxation; PDE5 degrades cGMP. cGMP relaxes pulmonary arterial smooth muscle via PKG. PDE5 degrades it — so PDE5 inhibitors (sildenafil, tadalafil) and the sGC stimulator riociguat both raise cGMP to vasodilate. Cross-link: pde5.
endothelin-1 → pulmonary-vasoconstriction — via ET-1 → ETA receptor → Gq → vasoconstriction + proliferation. Endothelin-1 is overexpressed in PAH; via the ETA receptor it drives vasoconstriction and vascular remodeling. Endothelin receptor antagonists (bosentan, macitentan) block it. Cross-link: eta.
prostacyclin-PGI2 → pulmonary-vasodilation — via PGI2 → IP receptor → Gs → cAMP → relaxation + antiproliferation. Prostacyclin is deficient in PAH; IP-receptor activation raises cAMP → vasodilation, antiproliferation, and antiplatelet effects. Prostacyclin analogs and the IP agonist selexipag supplement this axis (those agents not yet in the registry).
elevated-pulmonary-vascular-resistance → right-ventricular-failure — via chronic ↑PVR → RV pressure overload → hypertrophy → failure. The combined deficits (↓NO/cGMP, ↑ET-1, ↓PGI2) raise pulmonary vascular resistance and overload the right ventricle — the usual cause of death in PAH. The three drug classes each correct one axis and are often combined.