Vascular walls

Thrombolytic Enzymes. Although atherosclerosis and the accompanying vascular wall defects are ultimately responsible for such diseases as acute pulmonary embolism, arterial occlusion, and myocardial infarction, the lack of blood flow caused by a fibrin clot directly results in tissue injury and in the clinical symptoms of these devastating diseases (54). Thrombolytic enzyme therapy removes the fibrin clot by dissolution, and has shown promise in the treatment of a number of thrombo-occlusive diseases (60). 

Human bodies are constantly exposed to a plethora of bacteria, viruses, and other inflammatory substances. To combat these infections and toxic agents, the body has developed a carefully regulated inflammatory response system. Part of that response is the orderly migration of leukocytes to sites of inflammation. Leukocytes literally roll along the vascular wall and into the tissue site of inflammation. This rolling movement is mediated by reversible adhesive interactions between the leukocytes and the vascular surface. 

These interactions involve adhesion proteins called selectins, which are found both on the rolling leukocytes and on the endothelial cells of the vascular walls. Selectins have a characteristic domain structure, consisting of an N-terminal extracellular lectin domain, a single epidermal growth factor (EGR) domain, a series of two to nine short consensus repeat (SCR) domains, a single transmembrane segment, and a short cytoplasmic domain. Lectin domains, first characterized in plants, bind carbohydrates... 

Atherosclerosis A disease process of the arteries involving fatty plaque formation and inflammation in the vascular wall. 

Tissue distribution of lipo-preparations. The tissue distribution of lipid microspheres in normal and pathologic animals was studied. Research into liposomes of similar size suggested that lipid microspheres accumulated preferentially in the reticuloendothelial system, inflammatory sites, or certain tumors. The distribution of lipid microspheres to these tissues has been found in our studies (7,2). Interestingly, our study showed that lipid microspheres accumulated, particularly at high concentrations, in damaged vascular walls such as atherosclerotic vascular walls. 

It was found in animal and clinical studies that lipid microspheres accumulated particularly in arteriosclerotic and damaged vessel walls. Earlier studies (16,17) of lipid emulsions demonstrated also that lipid microspheres had an affinity to vascular walls, including capillaries, like chylomicrons. Shaw et al. reported that they had... 

Another prominent site of deposition of (5-amyloid fibrils with age and in AD is within the cerebrovasculature in areas of the brain prone to parenchymal amyloid deposition [137-139]. The peptide deposits along the surfaces of the smooth muscle cells of the vascular wall, resulting in the death of those cells and their replacement by amyloid fibrils, weakening the vascular wall. Endothelial cells are also affected [140]. The Dutch mutation in the APP precursor protein Q22E, within the (5-peptide sequence, produces a particularly fibrillogenic and toxic (to smooth muscle cells) peptide associated with primarily vascular deposition of mutant peptide and hemorrhagic vessel disease [137]. Thus, in addition to neuronal cells, the brain vascular smooth muscle cells are a pathologically relevant cell type. While the source of... 

Another metabolite of arachidonic acid is prostacyclin (PGI2). As with TxA2, PGI2 is produced continuously. Synthesized by vascular smooth muscle and endothelial cells, with the endothelium as the predominant source, PGI2 mediates effects that are opposite to those of TxA2. Prostacyclin causes vasodilation and inhibits platelet aggregation and, as a result, makes an important contribution to the antithrombogenic nature of the vascular wall. 

Sakharov, D.V., Jie, A.F.H., Bekkers, M.E.A., Emeis, J.J., and Rijken, D.C. (2001) Polylysine as a vehicle for extracellular matrix-targeted local drug delivery, providing high accumulation and long-term retention within the vascular wall. Aterioscler. Thromb. Vase. Biol. 21, 943-948. 

Fig. 4.1. Cellular model illustrating cell types in vascular wall involved in vasorelaxation induced by SERMs. Putative targets of SERMs are indicated within cyan tags. SERMs directly affect L-type VDCC, BK fil subunit in smooth muscle cells, and ER in endothelial cells. L-type VDCC L-type voltage-dependent calcium channel BK calcium-activated large conductance K+ channel PKG protein kinase G eNOS endothelial nitric oxide synthase GC soluble guanylate cyclase cGMP cyclic GM P V electrochemical membrane potential ER estrogen receptor. See text for further details...

Atherosclerosis, a disease of the vascular wall, is the substrate for the arterial forms of CVD. Atherosclerotic plaques exhibit a focal distribution along the arterial tree as a consequence of local conditions that favor their initiation and progression. Low or reversed shear stress, for example, contributes to plaque development, a process in which the regulation of several genes may be involved (Resnick and Gimbrone 1995). 

In conclusion, hemostasia intervenes in distinct critical steps of both the arterial and venous forms of CVD. The particulars, however, differ in each case, as confirmed by the different array of risk factors for CHD and VTED. The participation of the vascular wall is pivotal in explaining the focality of these processes. Within the vascular wall, the role of the endothelium is critical given its involvement in the origin of atherosclerosis and its influence on the development of VTED (for review see Cano and Van Baal 2001 Cano 2003). 

The vascular wall is an organ composed of an endothelium, smooth muscle, and fibroblasts. The endothelium has a privileged position to act as both a sensor and an effector. The endothelium governs remodeling by releasing growth... 

Some crucial steps in the biology of CVD have demonstrated sensitivity to estrogen agonists. Some of these actions have shown to be mediated by the classical pathway of estrogen receptors (ERs), though in other cases the involved mechanisms seem more complex and require the consideration of alternative options (Mendelsohn 2002). The available evidence concentrates on actions on lipids or on direct actions on the vascular wall. 

The vascular wall is a target for sexual hormones. In the particular case of estrogens, specific receptors have been found in both endothelium and vascular smooth muscle cells (VSMC) (Venkov et al. 1996 Karas et al. 1994). The trophic effects of estrogens on the endothelium have been advocated as crucial against initiation and promotion of atherosclerosis. Thus, cellular and animal models,... 

The other factor affecting the use of organic nitrates is nitrate tolerance, the mechanism of which is unclear. An early explanation of tolerance was thiol depletion [68] but that now seems unlikely as their is an abundance of thiol in most tissue [69]. A more likely explanation is down regulation of the enzymes involved in the biotransformation but few details are available. An interesting suggestion is that GTN induces increased production of superoxide from the vascular wall and tolerance is caused by reaction of NO, produced enzymatically from GTN, with superoxide to give peroxynitrite and then nitrate [70] (Eq. (16)). 

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