Endothelial cells control

Possible future pharmacological treatments could be based on the inhibition of proinflammatory mediators, prevention of adhesion between the leukocytes and endothelial cells, controlling the specific transduction pathway signals following cytokine production and promoting neovascularization. Strategies that block the activity of inflammation-induced enzymes, such as iNOS and COX-2 should also be investigated. 

Vascular gene therapy Transfer of dominant-negative receptors or suicide genes under the control of angiogenic endothelial cell specific promoters... 

Apelins and the Apelin Receptor. Figure 3 Scheme illustrating the hypothesised mechanisms of control of human (a) vasculartone and (b) cardiac contractility by apelin peptides ( ). In the vasculature, apelins (released via the small vesicles of the constitutive pathway) may act directly to activate apelin receptors on the underlying smooth muscle to produce vasoconstriction. This response may be modified by apelin peptides feeding back onto apelin receptors on endothelial cells to stimulate the release of dilators, such as nitric oxide. In heart, apelin peptides, released from endocardial endothelial cells, activate apelin receptors on cardiomyocytes to elicit positive inotropic actions. 

The protein-C pathway is one of the most important anticoagulant mechanisms. It is activated by thrombin. Thrombin binds to a cofactor in the membrane of endothelial cells, thrombomodulin (TM). TM bound thrombin no longer activates clotting factors or platelets but becomes an effective protein C (PC) activator. Activated PC (APC) forms a complex with Protein S, which inactivates FVIIIa and FVa. Hereby generation of Flla by the prothrombinase complex is inhibited (Fig. 9). Thus, the PC-pathway controls thrombin generation in a negative feedback manner. 

Lymphangiogenesis is the growth of lymphatic vessels, which is critically controlled by the interaction of VEGF-C and VEGF-D with the receptor VEGF-R3 on lymphatic endothelial cells. 

Pericytes are mural cells which stabilise capillaries and control functions of capillary endothelial cell properties. 

EC-SOD is a copper-zinc enzyme located on endothelial cell surfaces. It is believed that EC-SOD binds to the vasculature via specific glycosaminoglycans — probably heparan sulphate on the endothelium. The association of EC-SOD with endothelial cell surfaces may indicate a cell-specific protective role. Eig/ity per cent of SOD activity in control, noninflamed synovial fluid is due to EC-SOD and its concentration is decreased by 50% in RA fluid (Marklund etal., 1986). 

Oxidatively modified LDL up-regulates the surfece expression of VCAM-1 and intracellular adhesion molecule-1 (ICAM-1) in cultured endothelial cells, promoting the interactions between both cell types (Kume et al., 1992). This may play a pivotal role in the development of atherosclerosis by promoting the penetration of circulating monocytes into the suben-dothelial space whilst inhibiting the mobility of resident macrophages. It has been previously demonstrated that ICAM-1, E-selectin, and VCAM-1 are up-regulated in the microvasculature of rheumatoid but not control synovium (Corkill et al., 1991 Koch et al., 1991). The association between ox-LDL and increased expression of adhesion molecules in the inflamed synovium has yet to be studied. 

The endothelium has many diverse functions that enable it to participate in in-flammatoiy reactions (H27). These include modulation of vascular tone, and hence control of local blood flow changes in structure that allow leakage of fluids and plasma proteins into extravascular tissues local accumulation and subsequent extravasation into tissues of leukocytes and synthesis of surface molecules and soluble factors involved in leukocyte activation (B43). The endothelial cells themselves can modulate vascular tone by the release of vasoactive substances such as prostacyclin, nitric oxide (NO), ET. Endothelium-derived vasoactive substances... 

Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are members of a family of so-called natriuretic peptides, synthesized predominantly in the cardiac atrium, ventricle, and vascular endothelial cells, respectively (G13, Y2). ANP is a 28-amino-acid polypeptide hormone released into the circulation in response to atrial stretch (L3). ANP acts (Fig. 8) on the kidney to increase sodium excretion and glomerular filtration rate (GFR), to antagonize renal vasoconstriction, and to inhibit renin secretion (Ml). In the cardiovascular system, ANP antagonizes vasoconstriction and shifts fluid from the intravascular to the interstitial compartment (G14). In the adrenal cortex, ANP is a powerful inhibitor of aldosterone synthesis (E6, N3). At the hypothalamic level, ANP inhibits vasopressin secretion (S3). It has been shown that some of the effects of ANP are mediated via a newly discovered hormone, called adreno-medullin, controlling fluid and electrolyte homeostasis (S8). The diuretic and blood pressure-lowering effect of ANP may be partially due to adrenomedullin (V5). 

Returning to bacteria, PC also appears to play a role in infection of humans by pathogenic strains/species by allowing colonization and invasiveness due to interaction with appropriate receptors on host endothelial cells (reviewed by Harnett and Harnett, 1999). This may act as a double-edged sword, however, as the PC on the surface of the bacteria can be targeted by both the innate and adaptive immune responses and indeed such responses appear to play a role in the control of H. influenzae and S. pneumoniae, respectively, in humans (reviewed by Harnett and Harnett, 1999). 

Fig. 11.3 Effect of HU on ET-1 mRNA expression in the TrHBMEC (a) and EA-hy 926 (b) endothelial cells in culture. Quantitative real-time PCR was used to assess the level of ET-1 mRNA in at least four independent experiments in duplicate. Results are expressed in percentage of residual ET-1 mRNA expression for HU-treated cells as compared to the control (culture with or without cytokines). The TATA-binding protein mRNA was used as an internal control. The abbreviations are the same as in the legend for Figure 11.2.

Wick T, Kaye N, Jensen W. Unusually large von Willebrand factor multimers increase adhesion of sickle erythrocytes to human endothelial cells under controlled flow. N Engl J Med 1982 337 1584-1590. 

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