Abstract
Endothelin (ET) 1 is a potent vasoconstrictor peptide produced by vascular endothelial cells and implicated in various pathophysiologic states involving abnormal vascular tone. Homozygous ET-1 null mice have craniofacial and cardiac malformations that lead to neonatal death. To study the role of ET-1 in adult vascular physiology, we generated a mouse strain (ET-1flox/flox;Tie2- Cre mice) in which ET-1 is disrupted specifically in endothelial cells. ET-1 peptide levels in plasma, heart, lung, kidney, and brain homogenates were reduced by 65% to 80% in these mice. mRNA levels for ET Areceptors were unaltered except that the ETA receptor mRNA was upregulated in the heart. ET-1flox/flox;Tie2-Cre mice had mean blood pressures 10 to 12 mm Hg lower than genetic controls. In contrast, the blood pressure of mice systemically heterozygous for the ET-1 null allele (ET-1 mice) was unchanged compared with wild-type littermates. Despite the lower basal blood pressure, acute pharmacological responses to angiotensin II, captopril, phenylephrine, bradykinin, N-nitro-l-arginine methyl ester, and exogenous ET-1 were normal in ET-1;Tie2-Cre mice. These results support an essential role of endothelial-derived ET-1 in the maintenance of basal vascular tone and blood pressure. Normal pharmacological responses of ET-1;Tie2-Cre mice suggest that the renin-angiotensin system, the adrenergic system, and NO are not significantly altered by endothelial ET-1. Taken in conjunction with other lines of genetically altered mice, our results provide evidence for a paracrine vasoregulatory pathway mediated by endothelial cell-derived ET-1 acting on the vascular smooth muscle ETA receptor.
Original language | English (US) |
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Pages (from-to) | 121-128 |
Number of pages | 8 |
Journal | Hypertension |
Volume | 56 |
Issue number | 1 |
DOIs | |
State | Published - Jul 2010 |
Keywords
- Blood pressure
- Cre/loxP
- ET
- ET
- Endothelium
- Gene knockout
- Hypertension
ASJC Scopus subject areas
- Internal Medicine