Mechanisms of Pulmonary Vascular Dysfunction in Pulmonary Hypertension and Implications for Novel Therapies.

Pulmonary Hypertension (PH) is a serious disease characterized by various degrees of pulmonary vasoconstriction and progressive fibro-proliferative remodeling and inflammation of the pulmonary arterioles that lead to increased pulmonary vascular resistance, right ventricular hypertrophy and failure. Pulmonary vascular tone is regulated by a balance between vasoconstrictor and vasodilator mediators, and a shift in this balance to vasoconstriction is an important component of PH pathology, Therefore, the mainstay of current pharmacologic therapies centers on pulmonary vasodilation methodologies that either enhance vasodilator mechanisms such as the NO-cGMP and prostacyclin-cAMP pathways and/or inhibit vasoconstrictor mechanisms such as the endothelin-1, cytosolic Ca2+, and Rho-kinase pathways. However, in addition to the increased vascular tone, many patients have a "fixed" component in their disease that involves altered biology of various cells in the pulmonary vascular wall, excessive pulmonary artery remodeling, and perivascular fibrosis and inflammation. Pulmonary arterial smooth muscle cell (PASMC) phenotypic switch from a contractile to a synthetic and proliferative phenotype is an important factor in pulmonary artery remodeling. While current vasodilator therapies also have some anti-proliferative effects on PASMCs, they are not universally successful in halting PH progression and increasing survival. Mild acidification and other novel approaches that aim to reverse the resident pulmonary vascular pathology and structural remodeling and restore a contractile PASMC phenotype could ameliorate vascular remodeling and enhance the responsiveness of PH to vasodilator therapies.