Platelet-derived growth factor D induces cardiac fibrosis and proliferation of vascular smooth muscle cells in heart-specific transgenic mice
Platelet-derived growth factor D induces cardiac fibrosis and proliferation of vascular smooth muscle cells in heart-specific transgenic mice
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DOI：
10.1161/01.res.0000190590.31545.d4
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发表时间：
2005-11-11
影响因子：
20.1
通讯作者：
Eriksson, U
中科院分区：
文献类型：
--
作者：
Pontén, A;Folestad, EB;Eriksson, U
血小板衍生生长因子（PDGF）-D是PDGF/血管内皮生长因子家族的成员，可激活PDGF受体β（PDGF-β）。我们发现，PDGF-D在整个发育和成年期的心肌中高度表达，以及动脉血管平滑肌细胞（vSMC）。为了获得关于体内对PDGF-D的反应的进一步知识，我们产生了在心脏中过表达PDGF-D的活性核心结构域的转基因小鼠。转基因PDGF-D刺激心脏间质成纤维细胞和动脉vSMC增殖。这导致心脏纤维化，随后是扩张型心肌病和随后的心力衰竭。转基因小鼠还表现出血管重塑，包括血管扩张、SMC包被血管密度增加和vSMC增殖，导致中膜图尼卡增厚。动脉壁增厚是PDGF-D的一个独特特征，因为当PDGF-C在心脏中过表达时，这是看不到的。这些结果表明，PDGF-D通过PDGFR-β信号传导，是血管和结缔组织生长的有效调节剂，并可提供PDGFR-β的旁分泌和自分泌刺激。我们的数据提高了这种生长因子可能参与心脏纤维化和动脉粥样硬化的可能性。
Platelet-derived growth factor (PDGF)-D is a member of the PDGF/vascular endothelial growth factor family that activates PDGF receptor beta(PDGFR-beta). We show that PDGF-D is highly expressed in the myocardium throughout development and adulthood, as well as by arterial vascular smooth muscle cells (vSMCs). To obtain further knowledge regarding the in vivo response to PDGF-D, we generated transgenic mice overexpressing the active core domain of PDGF-D in the heart. Transgenic PDGF-D stimulates proliferation of cardiac interstitial fibroblasts and arterial vSMCs. This results in cardiac fibrosis followed by dilated cardiomyopathy and subsequent cardiac failure. Transgenic mice also display vascular remodeling, including dilation of vessels, increased density of SMC-coated vessels, and proliferation of vSMCs, leading to a thickening of tunica media. The thickening of arterial walls is a unique feature of PDGF-D, because this is not seen when PDGF-C is overexpressed in the heart. These results show that PDGF-D, via PDGFR-beta signaling, is a potent modulator of both vascular and connective tissue growth and may provide both paracrine and autocrine stimulation of PDGFR-beta. Our data raise the possibility that this growth factor may be involved in cardiac fibrosis and atherosclerosis.