Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension

• Published in: Microvascular Research 2004-09, Vol.68 (2), p.75-103
• Main Authors: Mandegar, Mehran, Fung, Yuan-Cheng B., Huang, Wei, Remillard, Carmelle V., Rubin, Lewis J., Yuan, Jason X.-J.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Blood Pressure; Bone Morphogenetic Protein Receptors, Type II; Calcium Signaling; Capillaries - pathology; Capillaries - physiopathology; Endothelium, Vascular - pathology; Familial and idiopathic pulmonary arterial hypertension; Feedback; Humans; Hypertension, Pulmonary - classification; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - physiopathology; Hypertrophy; Membrane Glycoproteins - physiology; Membrane Transport Proteins - physiology; Models, Biological; Muscle, Smooth, Vascular - pathology; Mutation; Nerve Tissue Proteins - physiology; Potassium Channels, Voltage-Gated - metabolism; Primary pulmonary hypertension; Protein-Serine-Threonine Kinases - genetics; Pulmonary Artery - pathology; Pulmonary Artery - physiopathology; Pulmonary Circulation; Pulmonary hemodynamics; Pulmonary vascular morphology; Pulmonary vascular resistance; Pulmonary Veins - pathology; Pulmonary Veins - physiopathology; Serotonin - physiology; Serotonin Plasma Membrane Transport Proteins; Vascular Resistance; Vasoconstriction
• ISSN: 0026-2862; 1095-9319
• DOI: 10.1016/j.mvr.2004.06.001

Pulmonary artery vasoconstriction and vascular remodeling greatly contribute to a sustained elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) in patients with pulmonary arterial hypertension (PAH). The development of PAH involves a complex and heterogeneous constellation of multiple genetic, molecular, and humoral abnormalities, which interact in a complicated manner, presenting a final manifestation of vascular remodeling in which fibroblasts, smooth muscle and endothelial cells, and platelets all play a role. Vascular remodeling is characterized largely by medial hypertrophy due to enhanced vascular smooth muscle cell proliferation or attenuated apoptosis and to endothelial cell over-proliferation, which can result in lumen obliteration. In addition to other factors, cytoplasmic Ca 2+ in particular seems to play a central role as it is involved in both the generation of force through its effects on the contractile machinery, and the initiation and propagation of cell proliferation via its effects on transcription factors, mitogens, and cell cycle components. This review focuses on the role played by cellular factors, circulating factors, and genetic molecular signaling factors that promote a proliferative, antiapoptotic, and vasoconstrictive physiological milieu leading to vascular remodeling.