Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
Circ Res. 2011 Jul 22;109(3):272-80. doi: 10.1161/CIRCRESAHA.111.240820. Epub 2011 Jun 2.
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.
To examine the role that placental growth factor (PGF) plays in the heart as a paracrine regulator of cardiac adaptation to stress stimulation.
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.
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.
心脏中心肌细胞和非心肌细胞之间旁分泌生长因子的相互作用对于编程适应性心肌肥厚至关重要，在这种适应性心肌肥厚中，心肌细胞大小、毛细血管密度和细胞外基质功能协调一致。
研究胎盘生长因子（PGF）在心脏中作为旁分泌调节剂在心脏对应激刺激的适应性中的作用。
PGF 在压力超负荷刺激后在心脏中被诱导，在心肌细胞和非心肌细胞中均有表达。我们生成了心脏特异性和成年诱导性 PGF 过表达转基因小鼠，并分析了 Pgf(-/-) 小鼠，以研究该因子在心脏疾病和旁分泌信号中的作用。虽然 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、更大的毛细血管密度增加和压力超负荷刺激下心脏成纤维细胞含量增加。PGF 转基因小鼠表现出更适应的心脏生长方式，对压力超负荷和神经内分泌刺激的衰竭迹象具有保护作用。相反，PGf(-/-) 小鼠在压力超负荷后 1 周内迅速死于心力衰竭，它们表现出不能上调血管生成的能力，并且心脏中成纤维细胞活性明显降低。从机制上讲，我们表明 PGF 对心肌细胞没有直接作用，而是通过诱导毛细血管生长和成纤维细胞增殖，通过中间旁分泌生长因子（如白细胞介素-6）作用于内皮细胞和成纤维细胞，从而支持更大的心脏肥厚。
PGF 是一种分泌因子，通过影响内皮细胞和成纤维细胞来支持压力超负荷期间的肥厚和心脏功能，这些细胞反过来通过额外的旁分泌因子刺激和支持心肌细胞。
