David X. Zhang, PhD

The overall emphasis of our laboratory is to understand signaling mechanisms in regulation of blood vessel reactivity and homeostasis under normal states as well as in diseases such as coronary artery disease (CAD), hypertension, and diabetes.

This regulation involves two major cell types in the vessel wall, namely the endothelial and smooth muscle cells. The endothelium is a single layer of cells lining the lumen of blood vessels. It regulates vascular tone and homeostasis through the release of various vasoactive factors. In response to either mechanical (e.g., flow or shear stress) or chemical (e.g., receptor agonists) cues, the endothelium synthesizes and releases nitric oxide (NO), prostacyclin (PGI2), and less well-understood endothelium-derived hyperpolarizing (EDH) factors such as metabolites of arachidonic acid and hydrogen peroxide (H2O2). These endothelial factors can diffuse out of the endothelial layer into the medial layer of the vessel wall and in turn regulate many functions of smooth muscle cells, including smooth muscle resting tone, relaxation and contraction response, and cell proliferation. In human coronary arterioles, H2O2 serves as a key flow-elicited vasodilator factor in the presence of CAD whereas other traditional factors (NO and PGI2) play a more significant role in vasodilation in the absence of CAD or its risk factors. Although both H2O2 and NO dilate coronary arterioles, each mediator has different or opposing non-vasomotor effects on vascular homeostasis and propensity for atherosclerosis. It remains largely unsolved how flow elicits two distinct classes of vasodilators in subjects with CAD versus those without. In addition, whether and how vascular smooth muscle of the human microcirculation changes function during CAD and other diseases remains poorly understood.

The current research is focused on the role of transient receptor potential (TRP) channels, a newly recognized family of calcium-permeable cation channels expressed in vascular endothelial cells, in mediating the conversion of vasodilator factors (NO/PGI2 in health and H2O2 in disease) in human coronary microcirculation. A second line of research relates to the function of smooth muscle K+ channels, such as Ca2+-activated K+ (KCa) and voltage-gated K+ (KV) channels, in arterioles from subjects with and without CAD. These smooth muscle K+ channels are the key end-effector of vasomotor control in the microcirculation. The studies are biomedically significant because they involve the use of human tissue in addition to animal models. Studies are performed with an integrated approach ranging from cellular and molecular techniques (Ca2+ imaging, protein mutagenesis), electrophysiology (patch clamping), to isolated vessel reactivity and in vivo vascular function assays.