Thrombospondin-1 and CD47 regulate blood pressure and cardiac responses to vasoactive stress.
Nitric oxide (NO) locally regulates vascular resistance and blood pressure by modulating blood vessel tone. Thrombospondin-1 signaling via its receptor CD47 locally limits the ability of NO to relax vascular smooth muscle cells and increase regional blood flow in ischemic tissues. To determine whether thrombospondin-1 plays a broader role in central cardiovascular physiology, we examined vasoactive stress responses in mice lacking thrombospondin-1 or CD47. Mice lacking thrombospondin-1 exhibit activity-associated increases in heart rate, central diastolic and mean arterial blood pressure and a constant decrease in pulse pressure. CD47-deficient mice have normal central pulse pressure but elevated resting peripheral blood pressure. Both null mice show exaggerated decreases in peripheral blood pressure and increased cardiac output and ejection fraction in response to NO. Autonomic blockade also induces exaggerated hypotensive responses in awake thrombospondin-1 null and CD47 null mice. Both null mice exhibit a greater hypotensive response to isoflurane, and autonomic blockage under isoflurane anesthesia leads to premature death of thrombospondin-1 null mice. Conversely, the hypertensive response to epinephrine is attenuated in thrombospondin-1 null mice. Thus, the matricellular protein thrombospondin-1 and its receptor CD47 serve as acute physiological regulators of blood pressure and exert a vasopressor activity to maintain global hemodynamics under stress.
Isenberg
Jeff S
JS
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, United States.
Qin
Yan
Y
Maxhimer
Justin B
JB
Sipes
John M
JM
Despres
Daryl
D
Schnermann
Jurgen
J
Frazier
William A
WA
Roberts
David D
DD
D000818:Animals; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology*; D051928:CD47 Antigen / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004452:Echocardiography; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000235:genetics / Q000502:physiology*; D007118:Immunoassay; D051379:Mice; D018345:Mice, Knockout; D012039:Regional Blood Flow; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000098:blood supply; D013312:Stress, Physiological / Q000502:physiology*; D019700:Thrombospondin 1 / Q000172:deficiency / Q000378:metabolism*
D051928:CD47 Antigen; C497894:CD47 protein, human; D019700:Thrombospondin 1; D000242:Cyclic AMP; D006152:Cyclic GMP