Low blood pressure in endothelial cell-specific endothelin 1 knockout mice.
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-1(flox/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 receptors were unaltered except that the ET(A) receptor mRNA was upregulated in the heart. ET-1(flox/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(dlox/+) mice) was unchanged compared with wild-type littermates. Despite the lower basal blood pressure, acute pharmacological responses to angiotensin II, captopril, phenylephrine, bradykinin, N(G)-nitro-L-arginine methyl ester, and exogenous ET-1 were normal in ET-1(flox/flox);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(flox/flox);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 ET(A) receptor.
Kisanuki
Yaz Y
YY
Departments of Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Tex75390-8584, USA. Yasushi.Kisanuki@osumc.edu
Emoto
Noriaki
N
Ohuchi
Takashi
T
Widyantoro
Bambang
B
Yagi
Keiko
K
Nakayama
Kazuhiko
K
Kedzierski
Rafal M
RM
Hammer
Robert E
RE
Yanagisawa
Hiromi
H
Williams
S Clay
SC
Richardson
James A
JA
Suzuki
Takashi
T
Yanagisawa
Masashi
M
D000483:Alleles; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation; D007022:Hypotension / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D044022:Receptor, Endothelin A / Q000096:biosynthesis / Q000235:genetics; D044023:Receptor, Endothelin B / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D011509:Proteoglycans; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C517044:endothelial cell-specific molecule-1, mouse