Angiotensin II-mediated microvascular thrombosis.
Hypertension is associated with an increased risk of thrombosis that appears to involve an interaction between the renin-angiotensin system and hemostasis. In this study we determined whether angiotensin II-mediated thrombosis occurs in arterioles and/or venules and assessed the involvement of type 1 (AT₁), type 2 (AT₂), and type 4 (AT₄) angiotensin II receptors, as well as receptors for endothelin 1 and bradykinin 1 and 2 in angiotensin II-enhanced microvascular thrombosis. Thrombus development in mouse cremaster microvessels was quantified after light/dye injury using the time of onset of the thrombus and time to blood flow cessation. Wild-type and AT₁ receptor-deficient mice were implanted with an angiotensin II-loaded ALZET pump for 2 weeks. Angiotensin II administration in both wild-type and ATAT₁ receptor-deficient mice significantly accelerated thrombosis in arterioles. Genetic deficiency and pharmacological antagonism of AT₁ receptors did not alter the thrombosis response to angiotensin II. Isolated murine platelets aggregated in response to low (picomolar) but not high (nanomolar) concentrations of angiotensin II. The platelet aggregation response to angiotensin II depended on AT₁ receptors. Antagonism of AT₂ receptors in vivo significantly prolonged the onset of angiotensin II-enhanced thrombosis, whereas an AT₄ receptor antagonist prolonged the time to flow cessation. Selective antagonism of either endothelin 1 or bradykinin 1 receptors largely prevented both the onset and flow cessation responses to chronic angiotensin II infusion. Our findings indicate that angiotensin II induced hypertension is accompanied by enhanced thrombosis in arterioles, and this response is mediated by a mechanism that involves AT₂, AT₄, bradykinin 1, and endothelin 1 receptor-mediated signaling.
Department of Molecular and Cellular Physiology, Louisiana State University Health Science Center, 1501 Kings Hwy, Shreveport, LA 71130-3932. dgrang@lsuhsc.edu.
Elena Y
EY
Senchenkova
Janice
J
Russell
Lidiana D
LD
Almeida-Paula
Joseph W
JW
Harding
D Neil
DN
Granger
D000804:Angiotensin II / Q000008:administration & dosage / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage; D000818:Animals; D065168:Bradykinin Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000503:physiopathology; D010974:Platelet Aggregation / Q000187:drug effects; D011945:Receptors, Angiotensin / Q000235:genetics; D018002:Receptors, Bradykinin / Q000032:analysis; D017466:Receptors, Endothelin / Q000032:analysis; D013927:Thrombosis / Q000139:chemically induced / Q000503:physiopathology*
D057911:Angiotensin Receptor Antagonists; D065168:Bradykinin Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D011945:Receptors, Angiotensin; D018002:Receptors, Bradykinin; D017466:Receptors, Endothelin; D000804:Angiotensin II