心脏神经肽Y能神经的促血管生成效应与机制

In recent years, enhancement of ischemic angiogenesis with angiogenic growth factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial cell growth factor (VEGF), has been attracting increasing attention as a promising new way to treat ischemic cardiovascular disease. Several studies have suggested that these factors may be therapeutically useful in the treatment of coronary heart disease. Angiogenesis, the process of new vessel formation or neovascularization is complex, and has been shown to be regulated by a balance of angiogenic factors and anti-angiogenic factors. Most of these factors are derived from the vascular wall or blood. Neuropeptide Y (NPY), a 36-amino-acid peptide, is present in sympathetic nerve endings around the blood vessels and is abundant in the heart. In human coronary, which are richly innervated by the sympathetic NPY-positive fibers. It is released during nerve activation and tissue ischemia and regulates vascular functions by the activation of multiple G-protein-coupled receptors named Y1 through Y6. Sympathetic nerve activation often accompanies tissue ischemia, which in turn stimulates angiogenesis and collateral vessels formation, but whether the nerves regulate neovascularization and whether NPY also has angiogenic actions by stimulating all three of the major angiogenic steps has nerve been determined. Here we have used the sympathetic nerves stimulating rat model and in vitro endothelial cell model of angiogenesis to investigate the angiogenic activity of NPY. The following observations demonstrated that NPY, a sympathetic cotransmitter, is angiogenic..①Stimulation of sympathetic nerves resulted in a gross angiogenic response characterized by the enlargement of granular endoplasmic reticulum or partial separation of endothelial cells from the subendothelial layer and the gradual apperance of cytoplasmic protrusions on the apical aspects of some endothelial cells (in about 10-15% of all observed endothelial cell profiles) in myocardium microvessel in rat; The expression of both neuropeptide Y receptor Y1 and Y2 mRNA in myocardium is also up-regulated by 56% and 82% respectively after 10 days stimulation of sympathetic nerve.②At low physiological concentrations, purified NPY promoted the proliferation and migration of cultured microvascular endothelial cells in a dose-dependent manner under serum-free conditions by using [3H]-TdR incorporation assay and wounding migration assay; NPY markedly induced the capillary tube formation of cultured microvascular endothelial cells which exhibited a typical morphological characteristics of angiogenesis in in vitro tube formation assay, and this effect has a dose-dependent manner. ③The expression of NPY receptor Y2 mRNA was markedly up-regulated in cultured microvascular endothelial cells treated with purified NPY in a dose-dependent manner in the process of capillary tube formation by using RT-PCR assay, but NPY receptor Y1 mRNA expression was unchanged. Taken together, these results strongly suggest that NPY positively affects angiogenic cascade, cell proliferation, migration, and capillary tube formation by activation of NPY receptor Y2.In summary, these findings indicate that NPY is a neurogenic mediator of angiogenesis by activation of it's angiogenic Y2 receptor system, treatment with NPY-based angiogenic drugs may enhance this process and offer a potential new therapy for ischemic cardiovascular diseases.

采用交感神经电刺激动物模型、细胞培养及分子生物学检测方法，探讨神经肽Y在心脏⒀苣谄は赴谋泶锕媛杉岸晕⒀芄剐透慕ǖ挠跋欤谎芯可窬腨的促血管生成效应与机制，鉴定出新的促血管生成因子。有助于阐明心脏肽能神经的生物学效应及血管生成反应的调控机理，为促血管生成疗法提供理论依据，为防治缺血性心脏病开辟新途径。