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Department of Physiology, Jefferson Medical College Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA; and
* Department of Molecular and Cellular Physiology, Louisiana State University Medical Center, Shreveport, Louisiana 71130, USA
1Correspondence: Department of Physiology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107-6799, USA. E-mail: Rosario.Scalia{at}mail.tju.edu
Vascular endothelial growth factor (VEGF) is an endothelium-specific secreted protein that induces vasodilation and increases endothelial release of nitric oxide (NO). NO is also reported to modulate leukocyte–endothelium interaction. Therefore, we hypothesized that VEGF might inhibit leukocyte–endothelium interaction via increased release of NO from the vascular endothelium. We used intravital microscopy of the rat mesenteric microcirculation to measure leukocyte–endothelium interactions 2, 4, and 24 h after systemic administration of VEGF to the rat (120 µg/kg, i.v., bolus). Superfusion of the rat mesentery with either 0.5 U/ml thrombin or 50 µM L-NAME consistently increased the number of rolling, adhering, and transmigrated leukocytes (P<0.01 vs. control mesenteries superfused with Krebs-Henseleit buffer). At 4 and 24 h posttreatment, VEGF significantly attenuated thrombin-induced and L-NAME-induced leukocyte rolling, adherence, and transmigration in rat mesenteric venules. In addition, adherence of isolated rat PMNs to thrombin-stimulated mesenteric artery segments in vitro was significantly reduced in mesenteric arteries isolated from VEGF-treated rats (P<0.001 vs. control rats). Direct measurement of NO demonstrated a threefold increase in basal NO release from aortic tissue of rats injected with VEGF, at 4 and 24 h posttreatment (P<0.01 vs. aortic tissue from control rats). Finally, systemic administration of VEGF to ecNOS-deficient mice failed to inhibit leukocyte–endothelium interactions observed in peri-intestinal venules. We concluded that VEGF is a potent inhibitor of leukocyte–endothelium interaction, and this effect is specifically correlated to augmentation of NO release from the vascular endothelium.—Scalia, R., Booth, G., Lefer, D. J. Vascular endothelial growth factor attenuates leukocyte–endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide.
Key Words: intravital microscopy • inflammation • neutrophil • microcirculation • mesentery
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