Nitric Oxide Inhibits Coronary Smooth Muscle Cell Proliferation
No, nitric oxide does not promote coronary smooth muscle cell proliferation—it actively inhibits it. 1
Mechanism of Antiproliferative Action
Nitric oxide functions as a potent inhibitor of vascular smooth muscle cell proliferation through multiple pathways. 1 The evidence from the American College of Cardiology and American Heart Association establishes that NO serves as both a vasodilator and an inhibitor of vascular smooth-muscle cell proliferation. 1
Primary Mechanisms
NO inhibits platelet activation and vascular smooth muscle cell proliferation as part of its fundamental cardiovascular protective functions. 1
The antiproliferative effect operates through cGMP-dependent and cGMP-independent pathways. 2, 3 NO activates soluble guanylyl cyclase to generate cGMP, which mediates growth inhibition, though additional mechanisms exist independent of this classical pathway. 4
NO increases ubiquitination and degradation of UbcH10, a ubiquitin-conjugating enzyme responsible for cell cycle progression, thereby inducing cell cycle arrest in smooth muscle cells. 2 This represents a direct antiproliferative mechanism where NO treatment decreases UbcH10 levels in a concentration-dependent manner. 2
S-nitrosation and inactivation of RhoA contributes to NO's antiproliferative effects. 3 NO decreases RhoA activation, which influences ERK signaling to increase the cyclin-dependent kinase inhibitor p21(Waf1/Cip1), ultimately inhibiting proliferation. 3
Clinical Relevance in Vascular Disease
Pathophysiology Context
In pulmonary arterial hypertension, decreased endothelial NOS expression correlates with excessive smooth muscle cell proliferation. 1 The American College of Cardiology notes that deficient NO production contributes to the abnormal proliferation/apoptosis ratio seen in pulmonary artery smooth muscle cells. 1
NO maintains thin vascular walls with large lumens and prevents neointimal hyperplasia following arterial injury. 4, 2 In animal models of balloon catheter injury, NO treatment profoundly decreases the injury-induced increase in UbcH10 levels and reduces neointimal formation by approximately 3-fold. 2
Therapeutic Implications
The antiproliferative properties of NO provide rationale for PDE-5 inhibitor therapy in pulmonary hypertension. 1 By preventing cGMP breakdown, these agents prolong NO's antiproliferative effects on pulmonary artery smooth muscle cells. 1
L-arginine supplementation can enhance NO production in disease states where endothelial dysfunction creates functional arginine deficiency. 1, 4 The American College of Chest Physicians notes that chronic L-arginine administration ameliorates pulmonary hypertension and vascular remodeling in experimental models. 1
Important Clinical Distinctions
A critical caveat: constitutively synthesized NO at physiologic levels may not regulate endothelial cell proliferation, whereas high NO production from inducible NOS can inhibit growth. 5 The antiproliferative effects require sustained exposure to NO concentrations ≥100 μM and occur after long-term treatment (18-96 hours). 5
In contrast to NO's antiproliferative action, angiotensin II is the most potent endogenous mitogen driving coronary smooth muscle cell proliferation. 6 This creates a pathophysiologic balance where impaired NO signaling combined with increased angiotensin II activity promotes the vascular smooth muscle proliferation seen in atherosclerosis and restenosis. 6