Direct evidence of leukocyte adhesion in arterioles by angiotensin II.
Although leukocytes adhere in arteries in various vascular diseases, to date no endogenous proinflammatory molecule has been identified to initiate leukocyte adhesion in the arterial vasculature. This study was undertaken to assess angiotensin II (Ang II)-induced leukocyte adhesion in arterioles in vivo. Rats received intraperitoneal injections of Ang II; 4 hours later, leukocyte recruitment in mesenteric microcirculation was examined using intravital microscopy. Ang II (1 nM) produced significant arteriolar leukocyte adhesion of mononuclear cells. Using function-blocking monoclonal antibodies (mAbs) against different rat cell adhesion molecules (CAMs), we discovered that this effect was dependent on P-selectin and beta(2)-integrin. In postcapillary venules, Ang II also induced leukocyte infiltration, which was reduced by P-selectin and by beta(2)- and alpha(4)-integrin blockade. Interestingly, neutrophils were the primary cells recruited in venules. Although beta(2)-integrin expression in peripheral leukocytes of Ang II-treated animals was not altered, it was increased in peritoneal cells. Immunohistochemical studies revealed increased P-selectin, E-selectin, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) expression in response to Ang II in arterioles and venules. These findings provide the first evidence that Ang II causes leukocyte adhesion to the arterial endothelium in vivo at physiologically relevant doses. Therefore, Ang II may be a key molecule in cardiovascular diseases in which leukocyte adhesion to the arteries is a characteristic feature.
Alvarez
Angeles
A
Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Av. Blasco Ibañez, 17, E-46010 Valencia, Spain.
Cerdá-Nicolás
Miguel
M
Naim Abu Nabah
Yafa
Y
Mata
Manuel
M
Issekutz
Andrew C
AC
Panés
Julián
J
Lobb
Roy R
RR
Sanz
Maria-Jesus
MJ
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000166:cytology; D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D039441:Integrin alpha4 / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000166:cytology* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014699:Venules / Q000166:cytology
D018821:CD18 Antigens; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D039441:Integrin alpha4