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 journalArticle

77 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 1 2010

Keywords

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

ASJC Scopus subject areas

  • Internal Medicine

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  • Cite this

    Kisanuki, Y. Y., Emoto, N., Ohuchi, T., Widyantoro, B., Yagi, K., Nakayama, K., Kedzierski, R. M., Hammer, R. E., Yanagisawa, H., Williams, S. C., Richardson, J. A., Suzuki, T., & Yanagisawa, M. (2010). Low blood pressure in endothelial cell-specific endothelin 1 knockout mice. Hypertension, 56(1), 121-128. https://doi.org/10.1161/HYPERTENSIONAHA.109.138701