Grover Theresa R, Parker Thomas A, Markham Neil E, Abman Steven H
Pediatric Heart Lung Center and Department of Pediatrics, University of Colorado School of Medicine, Denver, CO 80045, USA.
Am J Physiol Lung Cell Mol Physiol. 2005 Aug;289(2):L315-21. doi: 10.1152/ajplung.00038.2005. Epub 2005 Apr 15.
We have previously shown that lung VEGF expression is decreased in a fetal lamb model of PPHN and that VEGF165 inhibition causes severe pulmonary hypertension in fetal lambs. Therefore, we hypothesized that treatment with rhVEGF165 would preserve endothelium-dependent vasodilation and reduce the severity of pulmonary vascular remodeling in an experimental model of PPHN. We studied the effects of daily intrapulmonary infusions of rhVEGF after partial ligation of the ductus arteriosus (DA). We performed surgery in 24 late-gestation fetal lambs and placed catheters in the main pulmonary artery, left atrium, and aorta for pressure measurements and in the left pulmonary artery for drug infusions. A pressure transducer was placed around the LPA to measure blood flow to the left lung (Qp), and the DA was surgically constricted to induce pulmonary hypertension. rhVEGF165 or vehicle was infused for 7 or 14 days. ACh or 8-BrcGMP was infused on days 2 and 13 to assess endothelium-dependent and -independent vasodilation, respectively. ACh-induced vasodilation was reduced in PPHN lambs after 14 days (change in Qp from baseline, 106% vs. 11%). In contrast, the response to ACh was preserved in lambs treated with rhVEGF (change in Qp, 94% vs. 90%). Pulmonary vasodilation to 8-BrcGMP was not altered in PPHN lambs or enhanced by VEGF treatment. rhVEGF treatment increased expression of lung eNOS protein and decreased pulmonary artery wall thickness by 34% vs. PPHN lambs. We conclude that VEGF165 preserves endothelium-dependent vasodilation, upregulates eNOS expression, and reduces the severity of pulmonary vascular remodeling in experimental PPHN.
我们之前已经表明，在持续性肺动脉高压（PPHN）的胎羊模型中肺血管内皮生长因子（VEGF）表达降低，并且VEGF165抑制会导致胎羊出现严重的肺动脉高压。因此，我们推测，在PPHN实验模型中，用重组人VEGF165（rhVEGF165）治疗可维持内皮依赖性血管舒张并减轻肺血管重塑的严重程度。我们研究了在动脉导管（DA）部分结扎后每日肺内输注rhVEGF的效果。我们对24只妊娠晚期胎羊进行手术，将导管置于主肺动脉、左心房和主动脉以测量压力，并置于左肺动脉以进行药物输注。在左肺动脉周围放置压力传感器以测量左肺血流量（Qp），并通过手术缩窄DA以诱导肺动脉高压。rhVEGF165或赋形剂输注7天或14天。在第2天和第13天分别输注乙酰胆碱（ACh）或8-溴环磷酸鸟苷（8-BrcGMP）以评估内皮依赖性和非内皮依赖性血管舒张。14天后，PPHN羔羊中ACh诱导的血管舒张降低（Qp相对于基线的变化，分别为106%和11%）。相比之下，用rhVEGF治疗的羔羊对ACh的反应得以维持（Qp变化，分别为94%和90%）。PPHN羔羊中对8-BrcGMP的肺血管舒张未改变，VEGF治疗也未增强。与PPHN羔羊相比，rhVEGF治疗增加了肺内皮型一氧化氮合酶（eNOS）蛋白的表达，并使肺动脉壁厚度降低了34%。我们得出结论，VEGF165可维持内皮依赖性血管舒张，上调eNOS表达，并减轻实验性PPHN中肺血管重塑的严重程度。
