Epidermal growth factor: a potent vasoconstrictor in experimental hypertension

We have tested the hypothesis that growth factor signaling pathways are aug mented in hypertension, a disease associated with vascular smooth muscle ce ll growth. Thoracic aorta was dissected from deoxycorticosterone acetate-sa lt (DOCA-salt) and one kidney, one clip (1K, 1C) hypertensive rats and from sham normotensive rats for use in isolated tissue bath experiments. Systol ic blood pressure was significantly higher in DOCA-salt and 1K, 1C than in normotensive sham rats: 192 +/- 7, 185 +/- 10, and 117 +/- 4 mmHg, respecti vely. Although virtually no contraction to epidermal growth factor (EGF) wa s observed in endothelium-denuded sham rat aorta [1 +/- 1% phenylephrine (P E) (10 mu mol/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 c ontraction to EGF was still observed in endothelium-intact aortic strips fr om 28-day DOCA-salt hypertensive rats. We also conducted concentration-resp onse curves to EGF on days 1, 3, 5, 7, 14, and 21 of DOCA-salt therapy. A s ignificant contraction to EGF in aorta from DOCA-salt rats was observed on day 14, when DOCA-salt rats had significantly higher blood pressure than sh am rats: 188 +/- 6 and 122 +/- 3 mmHg, respectively. Transforming growth fa ctor-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 r eceptor tyrosine kinase inhibitor 4,5-dianilinophthalimide (10 mu mol/ i), the mitogen-activated protein kinase kinase inhibitor PD-098059 (10 mu mol/ l), and the L-type voltage-gated calcium channel inhibitor diltiazem (1 mol /l), but not the cyclooxygenase inhibitor indomethacin (10 mu mol/l), virtu ally abolished EGF-induced contraction (85, 98, and 99% reduction, respecti vely). These data support a striking difference in EGF signaling between no rmotensive and hypertensive animals. Furthermore, they provide evidence tha t growth factors should be considered vasoconstrictors as well as growth mo dulators in hypertension.