Endogenous Neuropeptide Y and ischemic revascularization in rodents : sources and receptors
Tilan, Jason Ulip.
Thesis (Ph.D.)--Georgetown University, 2009.; Includes bibliographical references.; Text (Electronic thesis) in PDF format. Therapeutic revascularization of ischemic tissue in Peripheral Arterial Disease (PAD) is presently inadequate, leaving many of those affected with advancing limb ischemia and/or loss of limb function. In order to examine processes of vascular development in PAD, we built upon our previous work which established a role for the sympathetic neurotransmitter, Neuropeptide Y (NPY), in ischemic angiogenesis. NPY is potently angiogenic via its Y2 receptor (R) and is also a mitogen for vascular smooth muscle cells via Y1R. The purpose of this study was to further characterize the role of NPY in arteriogenesis and angiogenesis in hindlimb ischemia following femoral artery ligation (FAL) in rodents. We sought to determine the role of endogenous NPY and the time course in activation of the NPY system - the peptide, its receptors, and a serine protease, DPPIV. We also investigated the contribution of platelet-derived NPY to ischemic revascularization in 129Sv mice. In NPY+/+ Wistar rats, NPY-immunoreactivity (-ir) of platelet-poor plasma, reflective of sympathetic nerve release of the peptide, was increased by 24 hours post-FAL. This was followed by a rise in Y2R mRNA levels in gastrocnemius muscle, which remained ischemic within the first week. However, spontaneous recovery was observed via immunohistochemistry by 14 days, in parallel with increased platelet-rich plasma NPY-ir, which reflect platelet levels of the peptide. Simultaneously, Y1R mRNA expression in adductor muscle was upregulated. Recovery in ischemic NPY-/- mice was delayed within the first week and by 14 days, marked impairment in capillary angiogenesis was observed (P<0.01). Angiogenic response to FAL was similarly inhibited in NPY-/- and thrombocytopenic NPY+/+ mice. However, transfer of NPY+/+ platelets into NPY-/- mice fully restored the capillarity in ischemic tissue indicating that platelets are a complete angiogenic source of the peptide. These data suggest that endogenous NPY is important early in ischemic recovery and that there is temporal coordination in the NPY system between circulating NPY and local receptor expression. Furthermore, this is the first study to demonstrate platelet-derived NPY is critical for ischemic capillary angiogenesis in 129Sv mice, in part, due to enhanced proliferation of endothelial cells.
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