Endothelial independence

P2Y receptors that are found on endothelial cells elicit a Ca2+-dependent release of endothelium-dependent relaxing factor (EDRF) and vasodilation. A secondary activation of a Ca2+-sensitive phospholipase A2 increases the synthesis of endothelial prostacyclin, which limits the extent of intravascular platelet aggregation following vascular damage and platelet stimulation. The P2Y-mediated vasodilation opposes a vasoconstriction evoked by P2X receptors located on vascular smooth muscle cells. The latter elicit an endothelial-independent excitation (i.e. constriction). P2Y receptors are also found on adrenal chromaffin cells and platelets, where they modulate catecholamine release and aggregation respectively. 

Furchgott and Zawadzki [1] first discovered that endothelial cells release a substance(s) responsible for the relaxation of vascular smooth muscle by acetylcholine this substance was named endothelium-derived relaxing factor (EDRF). This epoch-making discovery answers the question raised for nearly one hundred years by pharmacologists about why vascular smooth muscle is relaxed by acetylcholine, which however elicits contraction of the other smooth muscles. Because of its instability, the true chemical nature of EDRF was not easily identified. Several years later, several research groups independently found that the biological activities and biochemical properties of EDRF were identical... 

An alternative pathway for activating the cascade has recently been demonstrated in which factor XII is absent from the reaction mixture [42-45]. Two different groups have isolated two different proteins, each of which seems to activate the HK-prekallikrein complex. One is heat-shock protein 90 [46] and the other is a prolylcarboxypeptidase [47]. Neither protein is a direct prekallikrein activator as is factor Xlla or factor Xllf because each activator requires HK to be complexed to the prekallikrein. In addition, the reaction is stoichiometric, thus the amount of prekallikrein converted to kallikrein equals the molar input of heat-shock protein 90 (or prolylcarboxypeptidase). These proteins can be shown to contribute to factor Xll-independent prekallikrein activation and antisera to each protein have been shown to inhibit the process. When whole endothelial cells are incubated with normal plasma or factor Xll-deficient plasma, the rate of activation of the deficient plasma is very much slower than that of the normal plasma, the latter being factor Xll-dependent [45]. Under normal circumstances (with factor XII present), formation of any kallikrein will lead to factor Xlla formation even if the process were initiated by one of these cell-derived factors. 

Ebnet K, Kaldjian EP, Anderson AO, Shaw S (1996) Orchestrated information transfer underlying leukocyte endothelial interactions. Annu Rev Immunol 14 155-177 Edinger AL, Blanpain C, Kunstman KJ, Wohnsky SM, Parmentier M, Dorns RW (1999) Functional dissection of CCR5 coreceptor function through the use of CD4-independent simian immunodeficiency virus strains. J Virol 73(5) 4062 073 Edwards TG, Hoffman TL, Baribaud E, Wyss S, LaBranche CC, Romano J, Adkinson J, Sharron M, Hoxie JA, Dorns RW (2001) Relationships between CD4 independence, neutralization sensitivity, and exposure of a CD4-induced epitope in a human immunodeficiency virus type 1 envelope protein. J Virol 75(ll) 5230-5239... 

Factors that predispose an individual to IHD are listed in Table 4—2. Hypertension, diabetes, dyslipidemia, and cigarette smoking are associated with endothelial dysfunction and potentiate atherosclerosis of the coronary arteries. The risk for IHD increases two-fold for every 20 mm Hg increment in systolic blood pressure and up to eight-fold in the presence of diabetes.5,6 Physical inactivity and obesity independently increase the risk for IHD, in addition to predisposing individuals to other cardiovascular risk factors (e.g., hypertension, dyslipidemia, and diabetes). 

P13. Pober, J. S., Bevilacqua, M. P., Mendrick, D. L., Lapierre, L. A., Fiers, W., and Gimbrone, M., Two distinct monokines, interleukin 1 and tumor necrosis factor, each independently induce biosynthesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells. J. Immunol. 137,1893-1896 (1986). 

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.

These molecules interact with the leukocyte integrins and thus are important during the later stages of the inflammatory response, which are independent of selectin function. The major molecules present on endothelial cells are shown in Table 3.3. 

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