Protection of angiotensin II-induced vascular hypertrophy in vascular smooth muscle-targeted receptor activity-modifying protein 2 transgenic mice.
The vasodilator and vascular regulatory peptide adrenomedullin (AM), a member of the calcitonin gene-related peptide family of peptides, is predicted to play a pivotal protective role in cardiovascular dysfunction. The principle AM (AM1) receptor is composed of a G protein-linked calcitonin receptor-like receptor and a receptor activity-modifying protein (receptor activity-modifying protein 2). There is little knowledge of the receptors via which AM acts in diseases. Using smooth muscle-targeted receptor activity-modifying protein 2 transgenic mice with increased vascular density of functional AM1 receptors, we demonstrate that receptor activity-modifying protein 2 transgenic mice are not protected against angiotensin II-induced hypertension or cardiac hypertrophy. However, vascular hypertrophy, together with vascular cell adhesion molecule 1 and monocyte chemotactic protein 1 expression, is significantly reduced in the aortic walls of transgenic mice, as determined by histological techniques. This indicates that the AM1 vascular smooth muscle receptor can mediate local protection in vivo. This is supported by proliferation studies in cultured smooth muscle cells. By comparison, levels of hypotension and inflammation in a shock model were similar to those in wild-type mice. Thus, a role of the AM1 receptor in the vasoactive component could not be detected, and evidence is provided to show that the hypotensive response to AM is subject to desensitization in vivo. The finding that the vascular smooth muscle AM1 receptor acts at a local level to protect against hypertension-induced vascular hypertrophy and inflammation provides evidence that targeting this receptor may be a beneficial therapeutic approach.
Cardiovascular Division, King's College London, Franklin-Wilkins Building, Waterloo Campus, London SE1 9NH, UK.
Lihuan
L
Liang
Christina W
CW
Tam
Gabor
G
Pozsgai
Richard
R
Siow
Natalie
N
Clark
Julie
J
Keeble
Knut
K
Husmann
Walter
W
Born
Jan A
JA
Fischer
Robin
R
Poston
Ajay
A
Shah
Susan D
SD
Brain
D053607:Adrenomedullin / Q000097:blood; D000804:Angiotensin II / Q000097:blood*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D006984:Hypertrophy; D007022:Hypotension / Q000378:metabolism / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide / Q000378:metabolism; D014657:Vasculitis / Q000378:metabolism / Q000503:physiopathology
D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D000804:Angiotensin II; D053607:Adrenomedullin