These experiments investigate interactions between cerebromicrovascular endothelial cells (EC) which constitute the blood-brain barrier (BBB) and peripheral blood cells and/or components. Adhesive interactions involving murine cerebrovascular EC and encephalitogenic T lymphocytes were up~regulated by the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (1L-1beta) and interferon-gamma (IFNgamma), and inhibited by transforming growth factor-beta (TGFbeta). Cerebrovascular EC lines were also derived from both spontaneously hypertensive (SHR) rats and normotensive Wistar-Kyoto (WKY) rats. Although both cell lines constitutively expressed similar levels of the adhesion molecule, intercellular adhesion molecule-1 (ICAM-1), SHR-derived EC were more sensitive than WKY-derived EC with regard to ICAM-1 up-regulation induced by suboptimal concentrations of TNFalpha, 1L-1beta and IFNgamma, as well as by lipopolysaccharide (LPS). Although both cell lines demonstrated similar maximal response at high cytokine concentrations, the level of ICAM-1 up-regulation to all concentrations of LPS was significantly greater in SHR-derived EC. Additional experiments examining the adhesion of syngeneic as well as allogeneic monocytes indicate similar increased responsiveness of cytokine- or LPS-treated EC derived from SHR rats vs.WKY rats. These results indicate a mechanism by which hypertension may be a predisposing factor to disorders (i.e., stroke) related to increased adhesive interactions between monocytes and endothelium. Experiments were also performed on EC derived from human brain. In addition to the aforementioned factors, it was observed that endothelin (ET-1, ET-2 and ET-3), a family of potent vasoconstrictive peptides, up-regulated ICAM-1 and VCAM-1 and induced the expression of E-selectin on these cells. Studies regarding ET-1 induced release of 51Cr from EC demonstrated alterations in endothelial """"""""permeability"""""""" coincident and proportional to effects seen on adhesion molecule expression, indicating additional functional parameters affected by this peptide. All the above findings implicate factors such as cytokines and vasoactive peptides in disorders involving recruitment, attachment and/or transvascular migration of blood cells at sites of inflammatory responses. The data demonstrate the enhanced release of proinflammatory factors such as TNF; and responsiveness (i.e., ICAM-1 expression or monocyte adhesion) to proinflammatory factors in aged and hypertensive rats, respectively. Such findings may explain how advanced age and hypertension act as risk factors for stroke (i.e., increase the likelihood of interactions between monocytes and endothelium leading to local thrombosis or hemorrhage).
