Upregulation of the apelin-APJ pathway promotes neointima formation in the carotid ligation model in mouse.
OBJECTIVE
To investigate apelin-APJ (angiotensin receptor-like 1) signalling in vascular remodelling, we have examined the pathophysiological response to carotid ligation in apelin knockout mice.


RESULTS
Apelin null animals compared with wild-type mice had significantly decreased neointimal lesion area (1.17 +/- 0.17 vs. 3.33 +/- 1.04 x 10(4) microm(2), P < 0.05) and intima/media ratio (0.81 +/- 0.23 vs. 1.49 +/- 0.44, P < 0.05), averaged over four sites 0.5-2 mm from the ligation. Exogenous apelin infusion rescued the apelin-KO phenotype, promoting neointima formation in the null animals. Apelin null animals showed decreased smooth muscle positive area in the neointima (82.3 +/- 2.4 vs. 63.9 +/- 8.4, P < 0.05), and a smaller percentage BrdU positive cells in the neointima and media (11.06 +/- 1.00 vs. 6.53 +/- 0.86, P < 0.05). Apelin mRNA expression increased initially (5.2-fold, P < 0.01) followed by increased apelin receptor expression (10.1-fold, P < 0.05) in the ligated artery. Cytochemistry studies localized apelin expression to luminal endothelial cells and apelin receptor upregulation to smooth muscle cells (SMC) in the media and neointima. In vitro experiments with cultured rat aortic SMC revealed that apelin stimulation increased migration. In contrast to the increased expression of apelin and apelin receptor in carotid remodelling, expression was not upregulated in the apoE high fat model, and correlated with the known disease-inhibitory effect in this model.


CONCLUSIONS
These data suggest that increased apelin receptor expression by SMC provides a paracrine pathway in injured vessels that allows endothelial-derived apelin to stimulate their division and migration into the neointima.
Kojima
Yoko
Y
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
Kundu
Ramendra K
RK
Cox
Christopher M
CM
Leeper
Nicholas J
NJ
Anderson
Joshua A
JA
Chun
Hyung J
HJ
Ali
Ziad A
ZA
Ashley
Euan A
EA
Krieg
Paul A
PA
Quertermous
Thomas
T
D054392:Adipokines; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000073861:Apelin; D000075244:Apelin Receptors; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002340:Carotid Artery Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002352:Carrier Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D036341:Intercellular Signaling Peptides and Proteins; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
D054392:Adipokines; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; D001057:Apolipoproteins E; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II