Platelet-derived growth factor β receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3′ kinase signaling

Platelet-derived growth factor (PDGF) isoforms lead to mitogenic, survival, and chemotactic responses in a variety of mesenchymal cell types during development and in the adult. We have studied the importance of phosphatidylinositol-3′ kinase (PI3K) signaling in these responses by mutating the PI3K-binding sites in the PDGF-β receptor by gene targeting in embryonic stem cells. Homozygous mutant mice developed normally; however, cells derived from the mutants were less chemotactic and had largely lost their ability to contract collagen gels in response to PDGF. Injection of a mast cell degranulating agent in mice led to a decrease in interstitial fluid pressure resulting in edema formation. In contrast to wild-type mice, mutant mice were unable to normalize the pressure after treatment with PDGF. Taken together, these observations suggest a function for PDGF signaling through PI3K in interstitial fluid homeostasis by modulating the tension between cells and extracellular matrix structures.

血小板衍生生长因子（Platelet-derived growth factor，PDGF）同工型可在发育及成年阶段的多种间充质细胞中诱导产生促有丝分裂、存活及趋化应答。本研究通过胚胎干细胞基因靶向技术，对PDGF-β受体上的磷脂酰肌醇-3′激酶（phosphatidylinositol-3′ kinase，PI3K）结合位点进行突变，以此探究PI3K信号通路在上述应答中的重要作用。纯合突变型小鼠发育正常；然而，源自突变体的细胞趋化能力减弱，且基本丧失了在PDGF刺激下收缩胶原凝胶的能力。向小鼠体内注射肥大细胞脱颗粒剂后，可导致间质液压力降低并引发水肿。与野生型小鼠相比，突变型小鼠在接受PDGF处理后无法使压力恢复至正常水平。综合上述观察结果，本研究提示PDGF通过PI3K信号通路，可通过调节细胞与细胞外基质结构间的张力参与间质液稳态维持。