Hypoxic pulmonary endothelial cells release epidermal growth factor leading to vascular smooth muscle cell arginase-2 expression and proliferation.
Hypoxic pulmonary endothelial cells release epidermal growth factor leading to vascular smooth muscle cell arginase-2 expression and proliferation.
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DOI：
10.14814/phy2.15342
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发表时间：
2022-06
影响因子：
2.5
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肺动脉高压（PH）的标志是血管重构。我们之前已经表明，人肺微血管内皮细胞（hPMVEC）对缺氧的反应是表皮生长因子（EGF）介导的受体酪氨酸激酶（EGF受体（EGFR））的激活，导致精氨酸酶-2（Arg 2）依赖性增殖。我们假设hPMVEC释放EGF可通过激活人肺动脉平滑肌细胞（hPASMC）上的EGFR导致Arg 2上调而导致hPASMC增殖。为了验证这一假设，我们使用了条件培养基（CM）从hPMVEC生长在常氧（NCM）或缺氧（HCM）。将人PASMC在常氧条件下与HCM或NCM孵育，HCM引起Arg 2和活细胞数的显著诱导。当用EGF中和抗体或EGFR阻断抗体产生HCM时，所得HCM不会诱导Arg 2或增加hPASMC中的活细胞数。向HCM中加入EGFR阻断抗体，可防止HCM诱导的Arg 2和活细胞数量增加。HCM诱导hPASMC EGFR的稳健磷酸化。当用针对EGFR的siRNA转染hPASMC时，HCM诱导的活细胞数增加被阻止。当用HCM酶拮抗剂nor-NOHA处理hPASMC时，HCM诱导的活细胞数量增加被阻止。这些数据表明，缺氧hPMVEC释放EGF，EGF激活hPASMC EGFR，导致Arg 2蛋白表达和活细胞数增加。我们推测EGF中和抗体或EGFR阻断抗体代表了预防和/或减轻缺氧相关PH中血管重塑的潜在治疗方法。我们假设人肺微血管内皮细胞（hPMVEC）释放表皮生长因子（EGF）可能通过激活hPASMC上的EGF受体（EGFR）导致Arg 2上调而导致人肺动脉平滑肌细胞增殖。我们的数据表明，缺氧hPMVEC释放EGF，激活hPASMC EGFR，导致Arg 2蛋白表达和活平滑肌细胞数量的增加。
The hallmark of pulmonary hypertension (PH) is vascular remodeling. We have previously shown that human pulmonary microvascular endothelial cells (hPMVEC) respond to hypoxia with epidermal growth factor (EGF) mediated activation of the receptor tyrosine kinase, EGF receptor (EGFR), resulting in arginase‐2 (Arg2)‐dependent proliferation. We hypothesized that the release of EGF by hPMVEC could result in the proliferation of human pulmonary arterial smooth muscle cells (hPASMC) via activation of EGFR on the hPASMC leading to Arg2 up‐regulation. To test this hypothesis, we used conditioned media (CM) from hPMVEC grown either in normoxia (NCM) or hypoxia (HCM). Human PASMC were incubated in normoxia with either HCM or NCM, and HCM caused significant induction of Arg2 and viable cell numbers. When HCM was generated with either an EGF‐neutralizing antibody or an EGFR blocking antibody the resulting HCM did not induce Arg2 or increase viable cell numbers in hPASMC. Adding an EGFR blocking antibody to HCM, prevented the HCM‐induced increase in Arg2 and viable cell numbers. HCM induced robust phosphorylation of hPASMC EGFR. When hPASMC were transfected with siRNA against EGFR the HCM‐induced increase in viable cell numbers was prevented. When hPASMC were treated with the arginase antagonist nor‐NOHA, the HCM‐induced increase in viable cell numbers was prevented. These data suggest that hypoxic hPMVEC releases EGF, which activates hPASMC EGFR leading to Arg2 protein expression and an increase in viable cell numbers. We speculate that EGF neutralizing antibodies or EGFR blocking antibodies represent potential therapeutics to prevent and/or attenuate vascular remodeling in PH associated with hypoxia. We hypothesized that the release of epidermal growth factor (EGF) by human pulmonary microvascular endothelial cells (hPMVEC) could result in the proliferation of human pulmonary arterial smooth muscle cells via activation of the EGF receptor (EGFR) on the hPASMC leading to Arg2 up‐regulation. Our data suggest that hypoxic hPMVEC do release EGF, which activates hPASMC EGFR leading to Arg2 protein expression and an increase in viable smooth muscle cell numbers.