Peripheral vascular disease (PVD, also known as Peripheral Arterial Disease, or PAD) is a common circulatory disorder directly caused by a reduction or complete occlusion of blood flow of artery the lower extremities (e.g., leg or feet). In 2013, about 8.5 million Americans aged ? 40 years are affected by PAD and associated with significant morbidity, mortality, and economic burden. Unfortunately, no effective cures are available for PVD. The present medical interventions include traditional drug treatment, physical therapy and/or surgical vessel graft, which is only able to temporally relieving the clinical symptoms and oftentimes, the limb ends up to be amputated when treatments are failed. Thus, it is in an urgent need to develop alternative strategies either to treat the damaged or to regenerate the lost limb. Here, we propose to pursue this by exploring a new role of Meis1 gene in regulating vascular remodeling using hindlimb ischemic mouse model. Meis1 (myeloid ecotropic viral integration site 1) gene belongs to the three amino-acid loop extension (TALE) subclass of homeobox gene families and it is a highly conserved transcription factor in all eukaryotes. Together with other homeobox factor, e.g., Hoxa9 and pre-B-cell leukemia homeobox 1 (Pbx1), Meis1 plays a crucial role in embryogenesis, hematogenesis, and embryonic angiogenesis during embryonic development, while in adult stage, Meis1 may involve homeostats, tumorigenesis, and cardiomyocytes proliferation. Up to date, little is known about the role of Meis1 in regulating arteriogenesis and angiogenesis under ischemic condition. Our preliminary study found that the endothelial cell (EC) specific knockout (KO) of Meis1 gene significantly increased blood flow of ischemic hindlimb in neonatal mice compared to wild type (WT) control. In addition, Meis1-KO also significantly attenuated necrotic/lost compared to control mice, suggesting that deletion of Meis1 gene in ECs provides significant protective effect against ischemia. Further analysis of vascular diameters implies that the improved blood flow in Meis-1 KO mice might be due to the enhanced arteriogenesis rather than angiogenesis. Taken together, we hypothesize that endothelial Meis1 gene negatively regulates arteriogenesis following hindlimb ischemia.
Three Specific Aims are proposed to test the hypothesis:
Aim 1 is to examine the temporospatial expression pattern of Meis1 gene in the nave, sham, and ischemic hindlimb during developmental stage.
Aim 2 is to determine whether endothelial-specific deletion of Meis1 gene enhances arteriogenesis, angiogenesis, and blood flow of ischemic hindlimb in Meis1 KO mice.
Aim 3 is to investigate whether administration of Meis1 inhibitors mimics the beneficial effects of Mei1 KO-promoted blood flow following hindlimb ischemia. Completion of these aims will provide a better mechanistic understanding of Meis1-regulated arteriogenesis and/or angiogenesis under ischemic condition. The results may also reveal a new potential therapeutic approach leading a new drug discovery and treatment of PVD.
Peripheral vascular disease (PVD, also known as Peripheral Arterial Disease, or PAD) is a common circulatory disorder directly caused by a reduction or complete occlusion of blood flow to the lower leg or feet. Our preliminary study found that the endothelial cell-specific deletion of Meis1 gene significantly increase blood flow and greatly attenuated the necrotic/lost toe after ischemia. The present study proposed to use Meis1 transgenic mice to better understand how Meis1 gene regulate vascular network under ischemic condition.
