Arterial occlusive diseases remain responsible for the leading causes of death and disability in Western nations and have a particularly high prevalence among the Veteran population. Current therapy depends upon invasive revascularization with techniques ranging from endovascular angioplasty and stenting to open surgical vein bypass. Unfortunately, some patients are anatomically poor candidates for invasive revascularization. Arteriogenesis is the vital process of collateral artery formation, which largely occurs in areas of pre-formed arterial interconnections remote from the effects of ischemia. Arteriogenesis should not be confused with angiogenesis, a well-studied and biologically distinct mechanism through which capillary density of an ischemic tissue bed is increased. Strategies focused on ?therapeutic angiogenesis? for revascularization have not been clinically successful to date. Evidence suggests that the most important factors to functional collateral development are mechanical forces - fluid shear stress and circumferential wall stress - which become increased in remote arterioles after the occlusion of a conductance artery. Unfortunately, as the vessel diameter increases, shear stress falls quickly and the impetus for growth dissipates before maximal conductance is restored. To date, the biochemical signaling mechanisms governing arteriogenesis remain largely unknown. This knowledge gap prevents development of molecular therapies that would enhance collateral growth, a conceptually important strategy for medical treatment of many vascular diseases. Nucleotides are released from cells in response to mechanical perturbations, such as increased shear stress, and function as signaling molecules. Extracellular nucleotides, acting through their receptors, activate vascular and inflammatory cells and promote their interaction, are mitogenic, and result in endothelial nitric oxide production. Our studies to date have demonstrated the P2Y2 receptor is necessary for normal collateral growth and blood flow recovery in a model of femoral artery ligation (FAL). We have also found that administration of intra-arterial nucleotides is beneficial to blood flow recovery after FAL. We therefore hypothesize that purinergic signaling governs arteriogenesis. Our hypothesis was formulated after a careful analysis of published work in the field and the generation of some key preliminary data in our own laboratory.
In Aim 1, we will measure nucleotide release after FAL and identify the changes in purinergic receptor expression during collateral artery growth in order to establish a link between purinergic signaling mechanisms and collateral development.
In Aim 2, we will investigate the role of purinergic signaling mechanisms in the initiation and maintenance of vascular inflammation which drives arteriogenesis. Our long term-goal is to develop a pharmacotherapy capable of enhancing collateral growth and providing a medical therapy for the effects of arterial occlusive disease. The critical insights gained through the completion of this research will enable directed pharmacological therapies for arterial occlusive disease in any vascular bed and represent a great stride toward providing medical therapy for our aging Veterans as well as the general population.
Prevalence of cardiovascular diseases in the United States is high, and is known to be even greater within its Veteran population. This may be due to a stronger presence of associated risk factors (such as smoking) and, among the Vietnam-Era Veterans, Agent Orange exposure (linked to development of vascular disease and diabetes). Currently available treatment for advanced arterial occlusive disease is procedure based and subject to high cost and high failure rates. Worse, many veterans are not suitable candidates for intervention, leaving them no effective options for revascularization. By completing the work that we propose, we will gain important insight into a critical mechanism for collateral growth which will pave the way for pharmacotherapy development. Such a therapy would have great impact on the functional status of veterans and nonveterans alike, potentially salvaging limbs and maintaining quality of life.
