Leukocyte-Dependent Responses of the Microvasculature to Chronic Angiotensin II Exposure

Abstract

Angiotensin II (AngII) contributes to the pathogenesis of hypertension and other cardiovascular diseases. AngII induces a pro-oxidative, pro-inflammatory, and pro-thrombogenic phenotype in vascular endothelial cells. Although the peptide promotes the recruitment of leukocytes and platelets and induces oxidative stress in the microvasculature, it remains unclear whether and how the blood cell recruitment is linked to the production of reactive oxygen species (ROS). In this study, we addressed the contributions of AngII type-1 receptors (AT1r), and gp91phox to the recruitment of leukocytes and platelets and ROS production in venules during chronic (2 wks) infusion of AngII in wild type (WT) and mutant mice. Intravital video microscopy was used to measure the adhesion and emigration of leukocytes, the adhesion of fluorescently labeled platelets, and dihydrorhodamine oxidation (a measure of oxidative stress) in cremaster muscle post-capillary venules. In WT mice, AngII infusion induced a time-dependent increase in the adhesion of leukocytes and platelets and enhanced ROS production in venules. These changes in blood cell adhesion and ROS production were not observed in AT1r−/− mice, in AT1r−/− bone marrow chimeras (blood cells deficient in AT1r), gp91phox−/−, gp91phox−/− chimeras (blood cells or endothelial cells deficient in gp91phox) and in WT mice rendered granulocytopenic via i.p injection of anti-mouse Gr-1 antibody. Thrombocytopenic WT mice (platelets depleted by i.p. injection of rabbit anti-mouse thrombocyte antiserum) responded similar to WT mice. These findings implicate leukocyte-associated AT1r and gp91phox in the induction of the pro-oxidative, proinflammatory and prothrombogenic phenotype assumed by microvessels that are chronically exposed to elevated AngII.

Formyl-Peptide Receptor 2/3/Lipoxin A 4 Receptor Regulates Neutrophil-Platelet Aggregation and Attenuates Cerebral Inflammation

“…The neutrophil count was increased in MCAo/R mice, and further exacerbated in MCAo/R Fpr2/3 −/− mice vs. WT MCAo/R mice (Table 1). No differences were noted in: platelet count (Table 1); the relative proportions of immature vs. mature platelets (Supplemental Figure 1A+B); 18,19 nor in the level of activation within these populations (Supplemental Figure 1C+D), 21 in any groups or genotypes.…”

Monocytes Are Recruited From Venules During Arteriogenesis in the Murine Spinotrapezius Ligation Model

“…The mechanisms of this signaling are largely unknown and may involve factors originating from leukocytes as well as the vessels themselves. Other studies have provided evidence to support roles for both reactive oxygen species(20) and angiogension II (Ang-II)(21) in activating venules to recruit inflammatory cells. Whether or not these potent signaling molecules are involved in communication between shear stress-activated arterioles and venules in muscle remains to be seen.…”

A critical role for both CD40 and VLA5 in angiotensin Il–mediated thrombosis and inflammation

“…and xylazine (7.5 mg/kg body weight, i.p. ), and cremaster muscle was prepared for intravital microscopic observation, as previously described (7). Three venular segments—100 μm in length and 22–36 μm in diameter—were selected for evaluation.…”