Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance, culminating in right ventricular dysfunction and ultimately death. Despite treatment with vasodilator drugs, PAH patients consistently report a low quality of life and worsening functional capacity with dyspnea and fatigue. Although pulmonary hemodynamics and right ventricular function are critical determinants of functional capacity in PAH, less is known regarding the role of peripheral mechanisms contributing to exercise intolerance such as skeletal muscle dysfunction and the muscle microcirculation. The microcirculation regulates vascular resistance and blood flow within skeletal muscle and thereby has marked impacts on exercise tolerance. Yet, little is known about skeletal muscle perfusion and its effects on muscle function, aerobic capacity, and exercise performance in PAH.

In a rodent model of PAH (SU5416+hypoxia; SuHx), we demonstrate a reduced proportion of oxidative (Type I) skeletal muscle fibers and provide novel preliminary evidence of enhanced vasoconstriction in isolated skeletal muscle arterioles, without evidence of impaired myogenic or vasodilatory capacity. As in other peripheral vascular diseases, the increased vasoconstriction in peripheral PAH vessels may be due to several factors including enhanced adrenergic receptor gene expression, or greater synthesis and release of endothelium vasoconstrictor agonists (e.g. endothelin-1, etc.). However, the mechanism(s) of enhanced vasoconstriction of skeletal muscle arterioles in PAH and its effect on skeletal muscle blood flow during an exercise stress are not known.

Therefore, we hypothesize that enhanced vasoconstriction of soleus muscle arterioles reduces functional hyperemia, contributing to exercise intolerance in the SuHx model of PAH. The specific aims for this project are as follows:

1. 1. We will determine whether SuHx rats demonstrate a significantly reduced functional capacity and exercise performance, compared to their healthy counterparts (controls; CON).

We will determine whether the presence of PAH alters regional perfusion (at rest and during exercise) and functional hyperemia (during exercise) of several different vascular beds, compared to CON.

1. We will elucidate the structural and functional mechanisms associated with impaired peripheral vasoreactivity/hemodynamics and exercise intolerance.

The proposed studies will systematically assess mechanisms of abnormal skeletal muscle microcirculatory control and tissue blood flow in an animal model of PAH, and are likely to develop new areas for therapy to enhance functional capacity and quality of life in PAH.