Angiogenesis:  We are studying differential responses of adult cardiac and skeletal muscle to angiogenic gene therapy, focusing on effects of VEGF and pleiotrophin on the vasculature.  This research has demonstrated that VEGF gene delivery can induce vascular growth in both ischemic and non-ischemic mouse skeletal muscle and myocardium.  The vascular response is extremely localized within micrometers of the VEGF source through a heparin-independent mechanism. Constitutive expression in skeletal muscle of excessive amounts of VEGF, even in only a small region of tissue, causes vascular overgrowth that leads to vascular malformations. We are currently studying this effect in the heart to determine if such exquisite dose response and microenvironmental control determine vessel growth pattern and morphology in cardiac muscle.                                                          

Cell therapy for myocardial infarction:   We are studying the therapeutic effects of implanting bone marrow-derived cells (BMCs) into mouse hearts after myocardial infarction (MI).  In collaboration with the Yeghiazarians lab, we have shown that injection of BMCs 3 days post-MI can preserve or partially restore left ventricular function.  We have also demonstrated that injection of a cell-free extract of lysed BMCs has a similar therapeutic effect, suggesting not only that BMC therapy may be beneficial by a paracrine mechanism, but also that the cells may simply die and thus deliver a bolus of therapeutic growth factors.  We are currently studying the effects of age and disease status on the donor BMCs.

Role of NO synthase in human endothelial progenitor cell function:  A related project is aimed at understanding the molecular basis of age- and disease-related impairment of endothelial progenitor cells (EPCs), a heterogeneous population of cells that are thought to be involved in several aspects of angiogenesis and endothelial maintenance.  We are studying endothelial nitric oxide synthase (eNOS)-dependent and eNOS-independent mechanisms of EPC migration toward angiogenic stimuli by VEGF and pleiotrophin, and are investigating the molecular mechanisms through which NO controls EPC migration and differentiation.  We are also investigating the correlation between eNOS activity and EPC function both ex vivo and in vivo, including the genetic manipulation of these cells to enhance or impair their functional profile. 

Endothelium-dependent vascular reactivity:  We have developed an ultrasound-based approach to measure flow-mediated vasodilation (FMD) in arteries of living rats, and have shown that FMD in the rat model is physiologically similar to that in humans.  We are currently using this system to study mechanisms underlying endothelium-dependent vascular reactivity, as well as the beneficial effects of dietary flavanols on endothelial function.  With the help of Dr. Glantz, we are examining how vascular function is impaired by brief exposure to low levels of cigarette second hand smoke.