Urocortin promotes the development of vasculitis in a rat model of thromboangiitis obliterans via corticotrophin-releasing factor type 1 receptors.
OBJECTIVE
Urocortin is a locally expressed pro-inflammatory peptide. Here we have examined the effects of urocortin on sodium laurate-induced peripheral arterial vasculitis in rats, modelling the mechanisms of thromboangiitis obliterans (TAO).


METHODS
Peripheral vasculitis in rats was induced by sodium laurate and graded by gross appearance on the 12th day after injection. Histological changes in rat femoral arteries were assessed by histopathology and transmission electron microscopy. Blood cell counts, blood rheology, blood coagulation and plasma urocortin, thromboxane B(2), prostaglandin E(2) and soluble intercellular adhesion molecule-1 levels were measured. Expression of urocortin, corticotrophin-releasing factor (CRF(1/2)) receptors, cyclooxygenase (COX)-2 and intercellular adhesion molecule-1 (ICAM-1) at both mRNA and protein levels were determined by RT-PCR and Western blot.


RESULTS
Rats showed grossly visible signs and symptoms of TAO on the 12th day after sodium laurate injection. In these rats, blood was in a hypercoagulable state; plasma urocortin, prostaglandin E(2) and soluble intercellular adhesion molecule-1 levels were elevated; and the expression of urocortin, CRF(1) and CRF(1alpha)-receptors, COX-2 and ICAM-1 in rat femoral arteries were markedly increased. Exogenous urocortin, given for 12 days after sodium laurate, exacerbated the hypercoagulable state and augmented expression of CRF(1alpha)-receptors, COX-2 and ICAM-1. These effects were abolished by a CRF(1)-receptor antagonist, NBI-27914, or a non-selective CRF-receptor antagonist, astressin, but not by the CRF(2)-receptor antagonist, antisauvagine-30, given with exogenous urocortin.


CONCLUSIONS
Urocortin exacerbated the hypercoagulable state and vasculitis in a model of TAO induced by sodium laurate in rats, via CRF(1)-receptors. COX-2 and ICAM-1 might also have contributed to this exacerbation.
Xu
Youhua
Y
Department of Pharmacology, Nanjing Medical University, Nanjing, China.
Zhang
Rongjian
R
Chen
Jie
J
Zhang
Qichun
Q
Wang
Juejin
J
Hu
Jue
J
Guan
Xiaowei
X
Jin
Lai
L
Fu
Hong
H
Gui
Bo
B
Guo
Yuanyuan
Y
Li
Shengnan
S
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001167:Arteritis / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D001777:Blood Coagulation / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D015232:Dinoprostone / Q000097:blood; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007850:Lauric Acids; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013919:Thromboangiitis Obliterans / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D013929:Thromboxane B2 / Q000097:blood; D054832:Urocortins / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D000099052:CRF Receptor, Type 1
C471210:2-methyl-4-(N-propyl-N-cycloproanemethylamino)-5-chloro-6-(2,4,6-trichloranilino)pyrimidine; D000814:Aniline Compounds; D007850:Lauric Acids; D010446:Peptide Fragments; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; C116607:antisauvagine 30; C030358:lauric acid; D018799:Intercellular Adhesion Molecule-1; C104416:astressin; D013929:Thromboxane B2; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D051546:Cyclooxygenase 2; D015232:Dinoprostone