Role of alpha1beta1-integrin in arterial stiffness and angiotensin-induced arterial wall hypertrophy in mice.
We examined the arterial phenotype of mice lacking alpha(1)-integrin (alpha(1)(-/-)) at baseline and after 4 wk of ANG II or norepinephrine (NE) administration. Arterial mechanical properties were determined in the carotid artery (CA). Integrin expression, MAPK kinases, and focal adhesion kinase (FAK) were assessed in the aorta. No change in arterial pressure was observed in alpha(1)(-/-) mice. Elastic modulus-wall stress curves were similar in alpha(1)(-/-) and alpha(1)(+/+) animals, indicating no change in arterial stiffness. The rupture pressure was lower in alpha(1)(-/-) mice, demonstrating decreased mechanical strength. Lack of alpha(1)-integrin was accompanied by an increase in beta(1)-, alpha(v)-, and alpha(5)-integrins but no change in alpha(2)-integrin. ANG II increased medial cross-sectional area of the CA in alpha(1)(+/+), but not alpha(1)(-/-), mice, whereas equivalent pressor doses of NE did not produce a significant increase in either group. In alpha(1)(+/+) mice, ANG II induced alpha(1)-integrin expression and smooth muscle cell (SMC) hypertrophy in the CA in association with increased aortic expression of alpha-smooth muscle actin and smooth muscle myosin heavy chain and phosphorylation of ERK1/2, p38 MAPK, and FAK. ANG II did not induce SMC hypertrophy or phosphorylation of p38 MAPK and FAK in alpha(1)(-/-) mice. A functional anti-alpha(1)-integrin antibody inhibited in vitro the ANG II-induced phosphorylation of FAK and p38 MAPK. In conclusion, alpha(1)(-/-) mice exhibit a reduced mechanical strength at baseline and a lack of ANG II-induced SMC hypertrophy. These results emphasize the importance of alpha(1)beta(1)-integrin in p38 MAPK and FAK phosphorylation during vascular hypertrophy in response to ANG II.
Louis
Huguette
H
Institut National de la Santé et de la Recherche Médicale, U684, Nancy, France.
Kakou
Augustine
A
Regnault
Veronique
V
Labat
Carlos
C
Bressenot
Aude
A
Gao-Li
Jacqueline
J
Gardner
Humphrey
H
Thornton
Simon N
SN
Challande
Pascal
P
Li
Zhenlin
Z
Lacolley
Patrick
P
D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000378:metabolism; D001794:Blood Pressure; D017536:Carotid Artery, Common / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004548:Elasticity; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D005838:Genotype; D006339:Heart Rate; D006984:Hypertrophy; D039423:Integrin alpha1 / Q000235:genetics / Q000378:metabolism*; D039222:Integrin alpha1beta1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism* / Q000494:pharmacology; D010641:Phenotype; D010766:Phosphorylation; D012421:Rupture; D013718:Tensile Strength; D014662:Vasoconstrictor Agents / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D039423:Integrin alpha1; D039222:Integrin alpha1beta1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D009638:Norepinephrine