Epidermal growth factor: a potent vasoconstrictor in experimental hypertension

Abstract

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 μmol/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-α, 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 μmol/l), the mitogen-activated protein kinase kinase inhibitor PD-098059 (10 μmol/l), and the L-type voltage-gated calcium channel inhibitor diltiazem (1 mol/l), but not the cyclooxygenase inhibitor indomethacin (10 μmol/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.

Uridine adenosine tetraphosphate-induced contraction is increased in renal but not pulmonary arteries from DOCA-salt hypertensive rats

“…Moreover, several reports have demonstrated that these signal transduction pathways are altered in various animal models, including mineralocorticoid hypertension (5,18,19,59). In the present study, we observed that Up 4 A-induced contraction was mark- edly suppressed by ERK inhibition.…”

PI3-Kinase Upregulation and Involvement in Spontaneous Tone in Arteries From DOCA-Salt Rats

“…13 Animals remained on the regimen for 4 weeks. Systolic blood pressures were measured using standard tail cuff methods.…”

“…13 Tissues were challenged with a maximal concentration of ␣ adrenergic agonist, phenylephrine (PE) (10 Ϫ5 mol/L). IC87114 concentration response curves were generated by adding increasing concentrations of IC87114 (1ϫ10 Ϫ9 to 3ϫ10 Ϫ4 mol/L) with measurements of spontaneous tone taken every 30 minutes.…”

Low [Mg 2+ ] e Enhances Arterial Spontaneous Tone via Phosphatidylinositol 3-Kinase in DOCA-Salt Hypertension

“…25 Postoperatively, DOCA-salt rats were given a solution of 1% NaCl and 0.2% KCl for drinking. Sham rats also received a uninephrectomy but no implant and drank normal tap water.…”