Reduced thrombus stability in mice lacking the alpha2A-adrenergic receptor.
Platelet activation plays a central role in hemostasis and thrombosis. Many platelet agonists function through G-protein-coupled receptors. Epinephrine activates the alpha(2A)-adrenergic receptor (alpha(2A)) that couples to G(z) in platelets. Although alpha(2A) was originally cloned from platelets, its role in thrombosis and hemostasis is still unclear. Through analysis of alpha(2A)-deficient mice, variable tail bleeding times were observed. In vitro, epinephrine potentiated activation/aggregation responses of wild-type but not alpha(2A)-deficient platelets as determined by flow cytometry and aggregometry, whereas perfusion studies showed no differences in platelet adhesion and thrombus formation on collagen. To test the in vivo relevance of alpha(2A) deficiency, mice were subjected to 3 different thrombosis models. As expected, alpha(2A)-deficient mice were largely protected from lethal pulmonary thromboembolism induced by the infusion of collagen/epinephrine. In a model of FeCl(3)-induced injury in mesenteric arterioles, alpha(2A)(-/-) mice displayed a 2-fold increase in embolus formation, suggesting thrombus instability. In a third model, the aorta was mechanically injured, and blood flow was measured with an ultrasonic flow probe. In wild-type mice, all vessels occluded irreversibly, whereas in 24% of alpha(2A)-deficient mice, the initially formed thrombi embolized and blood flow was reestablished. These results demonstrate that alpha(2A) plays a significant role in thrombus stabilization.
Pozgajová
Miroslava
M
Rudolf Virchow Center, Deutsche Forschungsgemeinschaft (DFG) Center for Experimental Biomedicine, the Institute of Pharmacology and Toxicology, University of Würzburg, Germany.
Sachs
Ulrich J H
UJ
Hein
Lutz
L
Nieswandt
Bernhard
B
D000818:Animals; D001018:Aortic Diseases / Q000209:etiology; D004195:Disease Models, Animal; D004617:Embolism / Q000139:chemically induced / Q000209:etiology; D006487:Hemostasis; D008641:Mesenteric Vascular Occlusion; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation; D011655:Pulmonary Embolism / Q000139:chemically induced / Q000209:etiology; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency / Q000502:physiology*; D013927:Thrombosis / Q000139:chemically induced / Q000209:etiology*
C547769:Adra2a protein, mouse; D018341:Receptors, Adrenergic, alpha-2