Microvessel mechanobiology in pulmonary arterial hypertension: cause and effect.

Abstract

Pulmonary arterial hypertension (PAH, or group 1 pulmonary hypertension) is a progressive, insidious, and fatal illness of the pulmonary microvasculature. Proliferative remodeling of the small resistance arteries results in an elevation of mean pulmonary arterial pressure (mPAP) and total pulmonary vascular resistance (PVR), increasing the workload on the right ventricle (RV) until it eventually fails.1 Although these hemodynamic parameters are useful for clinical diagnosis, alone they have limited prognostic value; furthermore, vasodilator therapy aimed at reduction of PVR has achieved only modest success, and increases in patient survival are attributed primarily to earlier diagnosis and intervention.2 These limitations have motivated research focused on identifying measurable physiological parameters that could both predict mortality and serve as measures for therapeutic efficacy. Decreased pulmonary arteriolar compliance (PAC) is a major factor contributing to the increased RV workload and failure in PAH.3–5 PAC measures a vessel’s ability to deform under loading, and as a blood vessel stiffens its compliance decreases. Total vessel compliance is estimated as stroke volume divided by pulse pressure (PP). This estimation alone is a strong predictor of survival in idiopathic and familial PAH.5 Although proximal artery stiffness has received a great deal of attention in hypoxic pulmonary hypertension and is important in increasing RV workload, changes in PAC affect the entire pulmonary vasculature with the largest portion of that change occurring in vessels distal to the lung hilum.6 Understanding how vascular remodeling changes PAC, especially in the distal vasculature where much of our knowledge on vessel mechanics is currently lacking, will allow us to link the cellular and molecular mediators commonly studied in PAH with the biomechanical changes that cause elevated pressures and RV failure. Pulmonary arterial smooth muscle cells (PASMCs) and adventitial fibroblasts decrease PAC by altering the composition, amount, and organization …