Regulation of the paracrine angiogenic function of cardiac myocytes by cardiomyoc

描述（由申请人提供）：新出现的观察表明，心肌细胞生长和心脏血管生成过程必须在整个生命过程中保持平衡，并且表明过度的心脏肥大和/或心脏血管生成不足是对压力的反应，导致心功能受损、心肌病和心力衰竭。心脏生长和血管生成之间的不平衡可能在多种形式的人类心力衰竭的发生和进展中发挥重要作用。有趣的是，最近的几项研究表明，心肌细胞本身以旁分泌方式调节心脏血管生长，以应对压力。然而，这种心肌细胞旁分泌功能（心肌细胞的血管生成潜能）的分子调控尚不清楚。我们的中心假设是，在导致心脏肥大的应激条件下，血小板衍生生长因子受体β (PDGFR-)是心肌细胞血管生成潜能的上游调节剂。为了支持这一假设，我们已经证明，暴露于压力过载应激下的心肌细胞特异性Pdgfrb敲除小鼠会出现心功能障碍、心室扩张和心力衰竭，并伴有冠状动脉微血管功能缺陷。这些发现表明，PDGFR-信号是心脏应激反应的重要介质，但迄今为止尚未被认识到。为了进一步了解PDGFR-信号作为心肌细胞血管生成潜能调节剂的作用，我们将使用PDGFR-敲除模型和靶向包括PDGFR-的抗癌药物（Aim 1）来确定心肌细胞PDGFR-信号是否调节冠状动脉血管生成，以应对导致心脏肥大的病理性应激源。我们将使用Pdgfrb敲除模型进一步确定心肌细胞PDFGR-信号是否需要促进冠状动脉血管生成，这伴随着出生后早期生活或成年后运动训练中观察到的生理性心脏生长（Aim 2）。最后，我们将利用缺失PDGFR-的体外培养心肌细胞模型，确定PDGFR-信号调控心肌细胞血管生成潜能的机制。通过本应用中提出的实验，我们的总体假设得到了证实，这表明心脏中的PDGFR-可能是评估和治疗人类心力衰竭的新领域，此外，可能为使用靶向PDGFR信号的药物治疗的癌症患者提供预防和/或治疗心脏毒性的策略。

DESCRIPTION (provided by applicant): Emerging observations indicate that the processes of cardiomyocyte growth and cardiac angiogenesis must remain balanced throughout life and suggest that excess cardiac hypertrophy and/or insufficient cardiac angiogenesis in response to stress leads to impaired cardiac function, cardiomyopathy, and heart failure. An imbalance between cardiac growth and cardiac angiogenesis may play an essential role in the development and progression of multiple forms of human heart failure. Intriguingly, several recent studies indicate that the cardiomyocyte itself functions in a paracrine fashion to regulate blood vessel growth in the heart in response to stress. However, the molecular regulation of this paracrine function of cardiomyocytes (the angiogenic potential of cardiomyocytes) is not well understood. Our central hypothesis is that under conditions of stress that lead to cardiac hypertrophy, platelet derived growth factor receptor beta (PDGFR-) is an upstream regulator of the angiogenic potential of cardiomyocytes. In support of this hypothesis, we have shown that cardiomyocyte specific Pdgfrb knockout mice exposed to pressure overload stress develop cardiac dysfunction, ventricular dilatation and heart failure, associated with defective coronary microvascular function. These findings demonstrate that PDGFR- signaling is an essential and heretofore unappreciated mediator of the cardiac stress response. To further understand the role of PDGFR- signaling as a regulator of the angiogenic potential of cardiomyocytes, we will determine if cardiomyocyte PDGFR- signaling regulates coronary angiogenesis in response to pathologic stressors that lead to cardiac hypertrophy using a Pdgfrb knockout model and also via administration of anti-cancer agents whose targets include PDGFR- (Aim One). We will further determine if cardiomyocyte PDFGR- signaling is required to promote coronary angiogenesis which accompanies physiologic cardiac growth observed in early postnatal life or in adult life in response to exercise training using a Pdgfrb knockout model (Aim Two). Finally, we will determine the mechanism(s) by which PDGFR- signaling regulates the angiogenic potential of cardiomyocytes using an in vitro model of cultured cardiomyocytes in which PDGFR- is deleted. Confirmation of our overall hypothesis through the experiments proposed in this application would suggest that PDGFR- in the heart may be a novel area of concern in evaluating and treating selected forms of human heart failure, and in addition, may inform strategies to prevent and/or treat cardiotoxicity in cancer patients treated with agents that target PDGFR signaling. PUBLIC HEALTH RELEVANCE: Studies proposed in this application will seek to understand the role of platelet derived growth factor beta (PDGFR-), a protein expressed on the cell surface of a number of cell types including heart muscle cells, in the regulation of blood vessel growth in the heart during heart muscle growth which occurs as a result of a variety of stressors, some of which are directly linked to the development of heart failure. Insights gained from this study may be used to develop novel therapeutic strategies for the treatment of human heart failure due to multiple etiologies, and may also be useful to help develop strategies to prevent clinical cardiac toxicity due to anti-cancer agents that target PDGFR signaling.