Basic Science Research Programs

Current and Planned Research Projects.  The primary research efforts of the Vascular Surgery section are focused peripheral artery disease.  Some of our current and planned studies are listed below.

CLINICAL INVESTIGATIONS 

§       A Quantitative and Functional Analysis of Progenitor/Cells in Peripheral Vascular Disease.  The purpose of this novel laboratory investigation is to identify deficits in number and proangiogenic function of bone marrow stem cell populations in patients with severe peripheral vascular disease. This study may offer new insights into role of endogenous stem cell populations in the pathophysiological process of atheroclerosis and may suggest more effective stem cell based therapies for cardiovascular disease. 

§       Improvement of Peripheral Arterial Function by Enhancement of the Nitric Oxide System.  Animal studies have shown an intact endothelial nitric oxide system is required for vascular adaptations to arterial occlusion.  Improved endothelial function in patients with vascular disease may enhance vascular dilation and elevate maximal flow capacity and provide an environment more conducive to compensation vascular growth.  The first studies will utilize an angiotensin converting enzyme inhibitor in hypertensive patients with peripheral arterial disease.

PRE-CLINICAL STUDIES 

§       Mechanisms by which endothelial dysfunction impairs natural collateral growth.  All the risk factors for vascular disease are associated with endothelial dysfunction.  Endothelial dysfunction is caused by excess oxidative stress and/or reduced nitric oxide bioavailability.  Available studies indicate the capacity for collateral growth is impaired in patients and animals with endothelial dysfunction.  Superoxide and nitric oxide can impact all of the processes known to be important in arterial remodeling, including the expression and activity of growth modulators and matrix proteases and cell growth (apoptosis, proliferation, hypertrophy) and migration.   Yet the specific mechanisms responsible for the impairment of compensatory vascular growth by endothelial dysfunction are unknown. 

§       Methods to reduce oxidative stress and enhance NO bioavailability in the context of vascular disease and endothelial dysfunction.  Contradictory studies exist regarding the effectiveness of various therapies to decrease oxidative stress or elevate nitric oxide in order to improve limb perfusion in peripheral artery disease.  There are multiple mechanisms by which oxidative stress may be elevated and nitric oxide levels depressed, but this has generally not been considered in clinical or preclinical studies.  We believe optimal therapy can only be achieved after identifying abnormalities in  specific enzymes and availability of cofactors and substrates.

§       Role of the local renin-angiotensin system in collateral growth and development.  Angiotensin II can be produced locally in the vascular wall and can modulate all of the processes involved in compensatory arterial remodeling through receptor dependent mechanisms.  The stimulus for collateral growth may directly modulate the expression and activity of essential components of the local renin angiotensin system within the arterial wall as well as receptor levels.  The regulation of this system may be involved in the impairment of collateral growth by endothelial dysfunction or by genetic differences between individuals.

§       Genetic basis for differences in the capacity for collateral growth. The capacity for collateral growth may be determined, at least in part, by genetics.  To investigate this hypothesis and the impact on potential therapies to enhance compensatory vascular growth in arterial insufficiency, we are utilizing rat strains with different capacities for vascular growth.

§       Role of bone marrow derived cells in natural compensation to arterial insufficiency and the impairment of collateral growth and angiogenesis.  It is not established if the impairment of compensatory vascular growth during endothelial dysfunction results from abnormalities in stem cell function or if improvement of endothelial function can enhance stem cell homing and incorporation within the vascular wall.  Such studies will have fundamental implications for future cell based therapies.