Endothelial/endothelium

Endothelial, endothelium The layer of epithelial cells that line the cavities of the blood and lymph vessels, the heart, and other cavities of the body. 

Three years later Robert F Furchgott discov ered that the relaxing of smooth muscles such as blood vessel walls was stimulated by an unknown substance produced in the lining of the blood vessels (the endothelium) He called this substance the endothelium-dependent relaxing factor or EDRF and in 1986 showed that EDRF was NO Louis J Ignarro reached the same conclusion at about the same time Further support was provided by Salvador Moncada who showed that endothelial cells did in deed produce NO and that the l arginine to l citrulline conversion was responsible... 

Vasodilating molecule(s) liberated from vascular endothelial cells in response to chemical substances (i.e., Acetylcholine, bradykinin, substance P, etc.) or mechanical stimuli (i.e., shear stress, transmural pressure, etc.). The EDRF includes NO, prostaglandin J2 (prostacyclin), and endothelium-derived hypeipolarizing factor (EDHF). 

The vascular endothelium plays an important role in regulation of vascular tone and permeability. Dilatation of arterioles to increase blood flow and constriction of endothelial cells of postcapillary venules causing exsudation of plasma constituents illustrates the complex nature of this cell type. Moreover, by expression of adhesion molecules and secretion of chemokines endothelial cells play an important role in the recruitment of leukocytes to the inflamed area. Endothelial cells express two basic types of adhesion molecules on their surface ... 

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... 

The release of NO from the endothelium is induced by various chemical substances, including acetylcholine polypeptides such as substance P, bradykinin, and arginine vasopressin histamine ATP/ADP a2-adrenoceptor agonists thrombin and Ca2+ iono-phores. NO formed in response to mechanical stimuli like shear stress or transmural pressure plays an important role in maintaining basal blood flow. Endothelial NO causes vasodilatation, decreased... 

Endothelial Nitric Oxide Synthase (eNOS) Endothelin Converting Enzyme Endothelins Endothelium... 

Figure 25-2. The formation and secretion of (A) chylomicrons by an intestinal cell and (B) very low density lipoproteins by a hepatic cell. (RER, rough endoplasmic reticulum SER, smooth endoplasmic reticulum G, Golgi apparatus N, nucleus C, chylomicrons VLDL, very low density lipoproteins E, endothelium SD, space of Disse, containing blood plasma.) Apolipoprotein B, synthesized in the RER, is incorporated into lipoproteins in the SER, the main site of synthesis of triacylglycerol. After addition of carbohydrate residues in G, they are released from the cell by reverse pinocytosis. Chylomicrons pass into the lymphatic system. VLDL are secreted into the space of Disse and then into the hepatic sinusoids through fenestrae in the endothelial lining.

It is accepted that oxidation of LDL is a key event in endothelial injury and dysfunction. Oxidised LDL (oxLDL) may directly injure the endothelium and trigger the expression of migration and adhesion molecules. Monocytes and lymphocytes interact with oxLDL and the phagocytosis which follows leads to the formation of foam cells, which in turn are associated with the alteration of the expression pattern of growth regulatory molecules, cytokines and pro-inflammatory signals. The proposed role of oxLDL in atherogenesis, based on studies in vitro, is shown in Fig. 2.1. 

Fig. 2.1 Sequence of events in atherogenesis and role of low-density lipoprotein. Native LDL, in the subendothelial space, undergoes progressive oxidation (mmLDL) and activates the expression of MCP-1 and M-CSF in the endothelium (EC). MCP-1 and M-CSF promote the entry and maturation of monocytes to macrophages, which further oxidise LDL (oxLDL). Ox-LDL is specifically recognised by the scavenger receptor of macrophages and, once internalised, formation of foam cells occurs. Both mmLDL and oxLDL induce endothelial dysfunction, associated with changes of the adhesiveness to leukoc)des or platelets and to wall permeability.

Chin et al. (1992) have su ested that oxidized LDL and high-density lipoprotein (HDL) inactivate endothelial cell-derived NO. NO inactivation was due to the oxidized lipids within the lipoprotein particles and was thought to be explained by a chemical reaction between the lipoproteins and NO. Other investigators have shown that relaxation of vascular smooth muscle by acetylcholine or bradykinin (endothelium-dependent vasodilators) is inhibited by LDL (Andrews etal., 1987). The role of NO in the modification of LDL is discussed in full detail in Chapter 2. 

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). 

Injury (either physical or chemical) to the comeal endothelial cells has a marked efiect on occular function as these cells are responsible for maintaining the thickness and clarity of the cornea, yet they cannot be replaced if damaged. Immunohistochemical studies have revealed that enzymatic antioxidant defences, SOD, CAT and GSHPx, are similarly distributed in the corneal epithelium and endothelium (Rao etal., 1985 Attala et d., 1987, 1988). Other antioxidants include ascorbate, carotenoids and vitamin E (Fleath, 1962). 

A relationship between polyol pathway activity and reduction in endothelium-dependent relaxation in aorta from chronic STZ-diabetic rats has recently been reported (Cameron and Cotter, 1992). In agreement with several previous studies (Oyama et al., 1986 Kamata et al., 1989), endothelial-dependent relaxation was defective in the diabetic rats but the deficit was prevented by prior treatment with an AR inhibitor. The mechanism underlying the defect has been speculated to be due to decreased production of endothelium-derived relaxing factor (EDRF) or nitric oxide, NO (Hattori et al., 1991). It has been speculated that these vascular abnormalities may lead to diminished blood flow in susceptible tissues and contribute to the development of some diabetic complications. NO is synthesized from the amino-acid L-arginine by a calcium-dependent NO synthase, which requires NADPH as a cofactor. Competition for NADPH from the polyol pathway would take place during times of sustained hyperglycaemia and... 

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