Mechanisms underlying the cerebral microvascular responses to angiotensin II-induced hypertension.
Angiotensin II (AngII) and AngII type-1 receptors (AT1r) have been implicated in the pathogenesis of hypertension and ischemic stroke. The objectives of this study was to determine if/how chronic AngII administration affects blood-brain barrier (BBB) function and blood cell adhesion in the cerebral microvasculature. AngII-loaded osmotic pumps were implanted in wild type (WT) and mutant mice. Leukocyte and platelet adhesion were monitored in cerebral venules by intravital microscopy and BBB permeability detected by Evans blue leakage. AngII (two week) infusion increased blood pressure in WT mice. This was accompanied by an increased BBB permeability and a high density of adherent leukocytes and platelets. AT1r (on the vessel wall, but not on blood cells) was largely responsible for the microvascular responses to AngII. Immunodeficient (Rag-1(-/-) ) mice exhibited blunted blood cell recruitment responses without a change in BBB permeability. A similar protection pattern was noted in RANTES(-/-) and P-selectin(-/-) mice, with bone marrow chimeras (blood cell deficiency only) yielding responses comparable to the respective knockouts. These findings implicate AT1r in the microvascular dysfunction associated with AngII-induced hypertension and suggest that immune cells and blood cell-associated RANTES and P-selectin contribute to the blood cell recruitment, but not the BBB failure, elicited by AngII.
Department of Molecular & Cellular Physiology Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
Shantel A
SA
Vital
Satoshi
S
Terao
Mutsumi
M
Nagai
D Neil
DN
Granger
D000804:Angiotensin II / Q000008:administration & dosage / Q000502:physiology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D018946:Chemokine CCL5 / Q000172:deficiency / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006973:Hypertension / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D007962:Leukocytes / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018715:Microscopy, Video; D055806:Microvessels / Q000473:pathology / Q000503:physiopathology; D019007:P-Selectin / Q000235:genetics / Q000502:physiology; D010973:Platelet Adhesiveness; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology; D018183:Transplantation Chimera
C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D018398:Homeodomain Proteins; D019007:P-Selectin; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C064658:RAG-1 protein