Bellik Lydia, Vinci Maria Cristina, Filippi Sandra, Ledda Fabrizio, Parenti Astrid
Laboratory of Vascular Pharmacology, Department of Preclinical and Clinical Pharmacology, University of Florence, Viale G. Pieraccini, 50139, Florence, Italy.
Br J Pharmacol. 2005 Oct;146(4):568-75. doi: 10.1038/sj.bjp.0706347.
We have previously shown that hypoxia makes vascular smooth muscle cells (VSMCs) responsive to placental growth factor (PlGF) through the induction of functional fms-like tyrosine kinase (Flt-1) receptors. The aim of this study was to investigate the molecular mechanisms involved in the PlGF effects on proliferation and contraction of VSMCs previously exposed to hypoxia (3% O2). In cultured rat VSMCs exposed to hypoxia, PlGF increased the phosphorylation of protein kinase B (Akt), p38 and STAT3; activation of STAT3 was higher than that of other kinases. In agreement with this finding, the proliferation of hypoxia-treated VSMCs in response to PlGF was significantly impaired by the p38 and the phosphatidylinositol 3-kinase inhibitors SB202190 and LY294002, respectively, and was almost completely prevented by AG490, a janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) inhibitor. Since hypoxia was able to reverse the vasorelaxant effect of PlGF into a vasoconstrictor response, the mechanism of this latter effect was also investigated. Significant Flt-1 activity was measured in isolated preparations from rat aorta exposed to hypoxia. Inhibitors of mitogen-activated protein kinase kinase, Akt and STAT3 induced a modest inhibition of the vasoconstrictor response to PlGF, while the p38 inhibitor SB202190 markedly impaired the PlGF-induced contractile response. These effects were selectively mediated by Flt-1 without any involvement of foetal liver kinase-1 receptors. These data are the first evidence that different intracellular pathways activated by Flt-1 receptor in VSMCs are involved in diverse biological effects of PlGF: while mitogen activated protein kinase kinase/extracellular signal regulated kinase(1/2) and JAK/STAT play a role in VSMC proliferation, p38 is involved in VSMC contraction. These findings may highlight the role of PlGF in vascular pathology.
我们之前已经表明，缺氧通过诱导功能性fms样酪氨酸激酶（Flt-1）受体，使血管平滑肌细胞（VSMC）对胎盘生长因子（PlGF）产生反应。本研究的目的是探讨PlGF对先前暴露于缺氧（3% O₂）环境下的VSMC增殖和收缩作用的分子机制。在培养的暴露于缺氧环境的大鼠VSMC中，PlGF增加了蛋白激酶B（Akt）、p38和信号转导子和转录激活子3（STAT3）的磷酸化；STAT3的激活高于其他激酶。与这一发现一致，p38和磷脂酰肌醇3激酶抑制剂SB202190和LY294002分别显著损害了缺氧处理的VSMC对PlGF的增殖反应，而janus酪氨酸激酶（JAK）/信号转导子和转录激活子（STAT）抑制剂AG490几乎完全抑制了该反应。由于缺氧能够将PlGF的血管舒张作用转变为血管收缩反应，因此也对后一种作用的机制进行了研究。在暴露于缺氧环境的大鼠主动脉分离制剂中检测到了显著的Flt-1活性。丝裂原活化蛋白激酶激酶、Akt和STAT3的抑制剂对PlGF诱导的血管收缩反应有适度抑制作用，而p38抑制剂SB202190则显著损害了PlGF诱导的收缩反应。这些作用是由Flt-1选择性介导的，而不涉及胎儿肝激酶-1受体。这些数据首次证明，VSMC中Flt-1受体激活的不同细胞内途径参与了PlGF的多种生物学效应：丝裂原活化蛋白激酶激酶/细胞外信号调节激酶（1/2）和JAK/STAT在VSMC增殖中起作用，而p38参与VSMC收缩。这些发现可能突出了PlGF在血管病理学中的作用。
