Priscilla Williams, a graduate student in Eduardo Silva’s lab, has received an AHA Western States Affiliate Pre-Doctoral Fellowship to research peripheral arterial disease. Peripheral arterial disease (PAD) is a debilitating condition associated with increased cardiovascular and cerebrovascular morbidity and mortality. Therapeutic angiogenesis offers a promising approach to treat PAD by the delivery of angiogenic factors and cells with the aim of restoring oxygen-rich blood perfusion to ischemic tissue. However, the limited survival and retention of transplanted cells present major clinical challenges. Priscilla’s research proposes an innovative strategy that promotes recruitment of circulating endothelial progenitor cells (EPCs) to the ischemic tissue.
Priscilla hypothesizes that local material-controlled delivery of sphingosine-1-phosphate (S1P) will recruit EPCs from circulation and provide effective therapeutic angiogenesis in murine ischemic hindlimbs. She plans to objectively test the central hypothesis by pursuing three specific aims. Aim 1 will investigate the effect of hypoxia (1% O2) on the angiogenic response to S1P stimulation in mature and progenitor endothelial cells in vitro. Our preliminary studies indicate that hypoxia alters the angiogenic response to S1P stimulation.
Aim 2 will elucidate the effects of hypoxia and S1P stimulation on SDF-1/CXCR4-directed migration of EPCs in vitro. She expects to determine the optimal S1P conditions required to stimulate EPC migration under hypoxia and initially establish the delivery scheme to be validated in vivo.
Aim 3 is to quantify the ability to stimulate EPC homing to ischemic tissue and promote in situ revascularization with spatiotemporally controlled delivery of S1P using a mouse model of hindlimb ischemia. She will transduce human EPCs to express eGFP/luciferase and provide a source of these cells in circulation via intravenous injection. This will enable detection of EPC homing to ischemia using IVIS.
She will evaluate therapeutic angiogenesis by means of blood vessel density, recovered blood flow perfusion using LDPI, and limb integrity. This greater understanding of human EPC homing and angiogenesis under hypoxia will help elucidate the mechanisms responsible for ischemic vascular diseases.
The fellowship provides a stipend for up to two years. Dr. Jan Nolta and Dr. Fitz-Roy Curry are also consultants on the project.