Impaired vasomotor function induced by the combination of hypertension and hypercholesterolemia.

Although it is well known that endothelial function is compromised in the presence of either hypertension (HTN) or hypercholesterolemia (HCh), less is known about whether and how the combination of these risk factors (HTN+HCh) results in impaired endothelium-dependent dilation (EDD). The aims of this study were to evaluate the influence of HTN+HCh on vasomotor function and to identify the mechanisms that underlie the altered vascular reactivity elicited by HTN+HCh. Endothelium-dependent and -independent vasomotor responses of aortic vessels were studied in mice with diet-induced HCh and/or HTN induced by chronic administration of either angiotensin II (AngII) or deoxycorticosterone acetate-salt. HTN+HCh elicited an impairment of EDD that appeared between each risk factor alone. Incubation with catalase resulted in more severe EDD impairment. Each risk factor enhanced vascular H2O2 production, but a larger response was noted with HTN+HCh. An attenuated EDD was not observed in AngII type 1a receptor deficient (AT1r(-/-)) mice, but AT1r(-/-) bone marrow chimeras exhibited more profound impairment compared with wild-type. HTN+HCh does not exert an additive effect of vasomotor dysfunction compared with either risk factor alone, and both H2O2 and blood cell-associated AT1r contribute to the impaired EDD responses in mice with HTN+HCh.

Roles of inflammation and the activated protein C pathway in the brain edema associated with cerebral venous sinus thrombosis.

BACKGROUND AND PURPOSE: Increased blood-brain barrier (BBB) permeability, brain edema, and hemorrhage are important consequences of cerebral venous sinus thrombosis (CVST). The objective of this study was to define the role of the protein C pathway in the BBB permeability and edema elicited by experimental CVST. The role of neutrophil recruitment was also evaluated. METHODS: Edema, BBB permeability, leukocyte-endothelial cell adhesion (LECA) and inflammatory cytokine levels were monitored in a murine model of CVST. The role of activated protein C (APC) was assessed in wild type mice (WT) receiving APC neutralizing antibody and in endothelial protein C receptor overexpressing mice (EPCR-tg). Neutrophil involvement was evaluated using an anti-CD18 antibody (Ab) and antineutrophil serum. RESULTS: Brain edema and increases in BBB permeability and LECA were noted 48 hours after CVST. APC immunoblockade exacerbated these responses, while EPCR-tg exhibited blunted responses, as did WT treated with either antineutrophil serum or the CD18 Ab. CONCLUSIONS: The protein C pathway protects the brain against the deleterious microvascular responses to CVST, a response that appears to be linked to the recruitment of inflammatory cells.