Low blood pressure in endothelial cell-specific endothelin 1 knockout mice

Yaz Y. Kisanuki, Noriaki Emoto, Takashi Ohuchi, Bambang Widyantoro, Keiko Yagi, Kazuhiko Nakayama, Rafal M. Kedzierski, Robert E Hammer, Hiromi Yanagisawa, S. Clay Williams, James A Richardson, Takashi Suzuki, Masashi Yanagisawa

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

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 languageEnglish (US)
Pages (from-to)121-128
Number of pages8
JournalHypertension
Volume56
Issue number1
DOIs
StatePublished - Jul 2010

Keywords

  • Blood pressure
  • Cre/loxP
  • ET
  • ET
  • Endothelium
  • Gene knockout
  • Hypertension

ASJC Scopus subject areas

  • Internal Medicine

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