Placental Growth Factor Regulates Cardiac Adaptation and Hypertrophy Through a Paracrine Mechanism
Placental Growth Factor Regulates Cardiac Adaptation and Hypertrophy Through a Paracrine Mechanism
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DOI：
10.1161/circresaha.111.240820
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发表时间：
2011-07-22
影响因子：
20.1
通讯作者：
Molkentin, Jeffery D.
中科院分区：
文献类型：
--
作者：
Accornero, Federica;van Berlo, Jop H.;Molkentin, Jeffery D.
目的：探讨胎盘生长因子(PGF)作为心脏应激适应的旁分泌调节因子在心脏中的作用。方法和结果：压力超负荷刺激后，心肌细胞和非心肌细胞均可表达胎盘生长因子(PGF)。我们建立了心脏特异性和成人可诱导的PGF过表达转基因小鼠，并分析了PGF(-/-)小鼠，以检查该因子在心脏病和旁分泌信号中所起的作用。尽管PGF转基因小鼠没有基线表型或毛细血管密度的变化，但它们确实表现出更大的心脏肥厚反应，毛细血管密度更大的增加，以及心脏中成纤维细胞含量对压力超负荷刺激的响应。PGF转基因小鼠表现出一种更适应心脏生长的类型，这种类型的心脏生长对压力超负荷和神经内分泌刺激的失败迹象具有保护作用。相反，PGF(-/-)小鼠在压力超负荷后1周内迅速死于心力衰竭，它们显示出无法上调血管生成，并且它们心脏中的成纤维细胞活性显著降低。从机制上讲，PGF对心肌细胞无直接作用，但通过诱导毛细血管生长和成纤维细胞增殖作用于内皮细胞和成纤维细胞，继而通过白介素6等中间旁分泌生长因子支持心肌肥大。结论：PGF是一种分泌因子，通过影响内皮细胞和成纤维细胞，进而通过附加旁分泌因子刺激和支持心肌细胞，从而支持压力超负荷时的心肌肥大和心功能。(中国保监会2011年决议；109：272-280。)
Rationale: Paracrine growth factor-mediated crosstalk between cardiac myocytes and nonmyocytes in the heart is critical for programming adaptive cardiac hypertrophy in which myocyte size, capillary density, and the extracellular matrix function coordinately.Objective: To examine the role that placental growth factor (PGF) plays in the heart as a paracrine regulator of cardiac adaptation to stress stimulation.Methods and Results: PGF is induced in the heart after pressure-overload stimulation, where it is expressed in both myocytes and nonmyocytes. We generated cardiac-specific and adult inducible PGF-overexpressing transgenic mice and analyzed Pgf(-/-) mice to examine the role that this factor plays in cardiac disease and paracrine signaling. Although PGF transgenic mice did not have a baseline phenotype or a change in capillary density, they did exhibit a greater cardiac hypertrophic response, a greater increase in capillary density, and increased fibroblast content in the heart in response to pressure-overload stimulation. PGF transgenic mice showed a more adaptive type of cardiac growth that was protective against signs of failure with pressure overload and neuroendocrine stimulation. Antithetically, Pgf(-/-) mice rapidly died of heart failure within 1 week of pressure overload, they showed an inability to upregulate angiogenesis, and they showed significantly less fibroblast activity in the heart. Mechanistically, we show that PGF does not have a direct effect on cardiomyocytes but works through endothelial cells and fibroblasts by inducing capillary growth and fibroblast proliferation, which secondarily support greater cardiac hypertrophy through intermediate paracrine growth factors such as interleukin-6.Conclusions: PGF is a secreted factor that supports hypertrophy and cardiac function during pressure overload by affecting endothelial cells and fibroblasts that in turn stimulate and support the myocytes through additional paracrine factors. (Circ Res. 2011; 109: 272-280.)