From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark (X.Z., R.P., D.E.V., S.F.V.); and Victor Chang Cardiac Research Institute and Faculty of Medicine and Life Sciences, University of New South Wales, Sydney, New South Wales, Australia (P.B., D.M.B., R.M.G.).
Arterioscler Thromb Vasc Biol. 2015 Nov;35(11):2451-9. doi: 10.1161/ATVBAHA.115.305919. Epub 2015 Sep 3.
Stimulation of cardiac α1A-adrenergic receptors (α1A-AR) has been proposed for treatment of heart failure, since it increases myocardial contractility. We investigated a different mechanism, induction of angiogenesis.
Four to 6 weeks after permanent coronary artery occlusion, transgenic rats with cardiomyocyte-specific α1A-adrenergic receptor overexpression had less remodeling than their nontransgenic littermates, with less fibrosis, hypertrophy and lung weight, and preserved left ventricular ejection fraction and wall stress (all P<0.05). Coronary blood flow, measured with microspheres, increased in the infarct zone in transgenic rats compared with nontransgenic littermates (1.4±0.2 versus 0.5±0.08 mL min(-1) g(-1); P<0.05), which is consistent with angiogenesis, as reflected by a 20% increase in capillary density in the zone adjacent to the infarct. The question arose, how does transgenic overexpression of a gene in cardiomyocytes induce angiogenesis? We identified a paracrine mechanism, whereby vascular endothelial growth factor-A mRNA and protein were increased in isolated transgenic cardiomyocytes and also by nontransgenic littermate cardiomyocytes treated with an α1A-agonist, resulting in angiogenesis. Conditioned medium from cultured cardiomyocytes treated with an α1A agonist enhanced human umbilical vein endothelial cell tubule formation, which was blocked by an anti-vascular endothelial growth factor-A antibody. Moreover, improved cardiac function, blood flow, and increased capillary density after chronic coronary artery occlusion in transgenic rats were blocked by either a mitogen ERK kinase (MEK) or a vascular endothelial growth factor-A inhibitor.
Cardiomyocyte-specific overexpression of the α1A-adrenergic receptors resulted in enhanced MEK-dependent cardiomyocyte vascular endothelial growth factor-A expression, which stimulates angiogenesis via a paracrine mechanism involving heterocellular cardiomyocyte/endothelial cell signaling, protecting against remodeling and heart failure after chronic coronary artery occlusion.
刺激心脏 α1A-肾上腺素能受体（α1A-AR）已被提议用于治疗心力衰竭，因为它可以增加心肌收缩力。我们研究了一种不同的机制，即诱导血管生成。
在永久性冠状动脉闭塞后 4 至 6 周，心肌细胞特异性 α1A-肾上腺素能受体过表达的转基因大鼠与非转基因同窝仔鼠相比，重塑程度较低，纤维化、肥大和肺重减少，左心室射血分数和壁应力保持不变（均 P<0.05）。用微球测量的冠状动脉血流量在转基因大鼠的梗死区增加，与非转基因同窝仔鼠相比（1.4±0.2 对 0.5±0.08 mL min(-1) g(-1)；P<0.05），这与血管生成一致，反映在梗死区附近的毛细血管密度增加了 20%。问题出现了，转基因过表达心肌细胞中的基因如何诱导血管生成？我们确定了一种旁分泌机制，即血管内皮生长因子-A mRNA 和蛋白在分离的转基因心肌细胞中增加，并且非转基因同窝仔鼠的心肌细胞用 α1A-激动剂处理时也增加，导致血管生成。用 α1A 激动剂处理的培养心肌细胞的条件培养基增强了人脐静脉内皮细胞小管形成，该作用被抗血管内皮生长因子-A 抗体阻断。此外，慢性冠状动脉闭塞后转基因大鼠的心脏功能改善、血流增加和毛细血管密度增加被丝裂原 ERK 激酶（MEK）或血管内皮生长因子-A 抑制剂阻断。
心肌细胞特异性过表达 α1A-肾上腺素能受体导致增强的 MEK 依赖性心肌细胞血管内皮生长因子-A 表达，通过涉及异体细胞（心肌细胞/内皮细胞）信号转导的旁分泌机制刺激血管生成，在慢性冠状动脉闭塞后防止重塑和心力衰竭。
