Florian J A, Watts S W
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824-1317, USA.
Am J Physiol. 1999 Mar;276(3):H976-83. doi: 10.1152/ajpheart.1999.276.3.H976.
We have tested the hypothesis that growth factor signaling pathways are augmented in hypertension, a disease associated with vascular smooth muscle cell growth. Thoracic aorta was dissected from deoxycorticosterone acetate-salt (DOCA-salt) and one kidney, one clip (1K, 1C) hypertensive rats and from sham normotensive rats for use in isolated tissue bath experiments. Systolic blood pressure was significantly higher in DOCA-salt and 1K, 1C than in normotensive sham rats: 192 +/- 7, 185 +/- 10, and 117 +/- 4 mmHg, respectively. Although virtually no contraction to epidermal growth factor (EGF) was observed in endothelium-denuded sham rat aorta [1 +/- 1% phenylephrine (PE) (10 micromol/l)-induced contraction], the maximal EGF-induced contraction was 45 +/- 7% in endothelium-denuded aorta from DOCA-salt hypertensive rats and 39 +/- 7% in aorta from 1K, 1C rats. Although slightly attenuated, a contraction to EGF was still observed in endothelium-intact aortic strips from 28-day DOCA-salt hypertensive rats. We also conducted concentration-response curves to EGF on days 1, 3, 5, 7, 14, and 21 of DOCA-salt therapy. A significant contraction to EGF in aorta from DOCA-salt rats was observed on day 14, when DOCA-salt rats had significantly higher blood pressure than sham rats: 188 +/- 6 and 122 +/- 3 mmHg, respectively. Transforming growth factor-alpha, an agonist of the EGF receptor, contracted DOCA-salt rat aorta (30 +/- 7% PE-induced contraction) but not sham aorta (3 +/- 3%). The EGF receptor tyrosine kinase inhibitor 4,5-dianilinophthalimide (10 micromol/l), the mitogen-activated protein kinase kinase inhibitor PD-098059 (10 micromol/l), and the L-type voltage-gated calcium channel inhibitor diltiazem (1 mol/l), but not the cyclooxygenase inhibitor indomethacin (10 micromol/l), virtually abolished EGF-induced contraction (85, 98, and 99% reduction, respectively). These data support a striking difference in EGF signaling between normotensive and hypertensive animals. Furthermore, they provide evidence that growth factors should be considered vasoconstrictors as well as growth modulators in hypertension.
在高血压（一种与血管平滑肌细胞生长相关的疾病）中，生长因子信号通路会增强。从醋酸去氧皮质酮-盐（DOCA-盐）和单肾单夹（1K，1C）高血压大鼠以及假手术正常血压大鼠身上解剖出胸主动脉，用于离体组织浴实验。DOCA-盐组和1K，1C组大鼠的收缩压显著高于正常血压假手术大鼠：分别为192±7、185±10和117±4 mmHg。尽管在去内皮的假手术大鼠主动脉中几乎未观察到对表皮生长因子（EGF）的收缩反应[苯肾上腺素（PE）（10 μmol/L）诱导的收缩为1±1%]，但在DOCA-盐高血压大鼠去内皮的主动脉中，EGF诱导的最大收缩为45±7%，在1K，1C大鼠的主动脉中为39±7%。在28天的DOCA-盐高血压大鼠完整内皮的主动脉条中，虽然收缩反应略有减弱，但仍可观察到对EGF的收缩反应。我们还在DOCA-盐治疗的第1、3、5、7、14和第21天对EGF进行了浓度-反应曲线实验。在第14天观察到DOCA-盐大鼠的主动脉对EGF有显著收缩反应，此时DOCA-盐大鼠的血压显著高于假手术大鼠：分别为188±6和122±3 mmHg。表皮生长因子受体的激动剂转化生长因子-α使DOCA-盐大鼠的主动脉收缩（PE诱导的收缩为30±7%），但未使假手术大鼠的主动脉收缩（3±3%）。表皮生长因子受体酪氨酸激酶抑制剂4,5-二苯胺基邻苯二甲酰亚胺（10 μmol/L）、丝裂原活化蛋白激酶激酶抑制剂PD-098059（10 μmol/L）和L型电压门控钙通道抑制剂地尔硫䓬（1 μmol/L），但非环氧化酶抑制剂吲哚美辛（10 μmol/L），几乎完全消除了EGF诱导的收缩（分别降低85%、98%和99%）。这些数据支持了正常血压和高血压动物之间表皮生长因子信号存在显著差异。此外，它们提供了证据表明在高血压中，生长因子应被视为血管收缩剂以及生长调节剂。
