Danielle J. McCullough, PhD
Department of Medicine, Brown University
830 Chalkstone Ave, Bldg 7
Providence, RI 02908
J. Danielle McCullough, PhD
Danielle (“Dani”) McCullough is currently a Postdoctoral Fellow at the Warren Alpert Medical School of Brown University. She is the Principal Investigator on a 5-month pilot project with the CPVB COBRE entitled “ Peripheral Blood Flow and Exercise Intolerance in Pulmonary Arterial Hypertension.”
Dr. McCullough graduated with joint degrees in Human Kinetics and Athletic Therapy from the University of Guelph (Ontario, Canada) and Sheridan College (Ontario, Canada), respectively. She went on to complete her Master’s in Human Performance at the University of Florida, where she also received her PhD in Exercise Physiology. Her doctoral work in Dr. Brad Behnke’s laboratory primarily focused on the pathophysiological relationship between microvascular structure and dysfunction and the implication(s) on hemodynamic control in diseased populations, with a secondary focus on how chronic exercise can be used as a therapeutic modality in the prevention and management of common pathologies. In 2013, she joined the Vascular Research Laboratory as a postdoc under the mentorship of Dr. Gaurav Choudhary, and is applying her background in exercise physiology to identify and elucidate peripheral mechanisms associated with a reduced exercise tolerance in pulmonary hypertension.
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:
- We will determine whether SuHx rats demonstrate a significantly reduced functional capacity and exercise performance, compared to their healthy counterparts (controls; CON).
- We will elucidate the structural and functional mechanisms associated with impaired peripheral vasoreactivity/hemodynamics and exercise intolerance.
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.
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.
Nothing to report, data has been collected but has to be analyzed.
Dr. Gaurav Choudhary, MD
Associate Professor of Medicine, Alpert Medical School of Brown University