**13. Endothelial dysfunction**

atherosclerosis by increasing smooth muscle cell susceptibility to insulin-like growth fac‐

The foam cells within the plaque are an expression of integrative participation within such schemes of complicating plaque formation as realized by such phenomena as lipid core accumulation, chemotaxis, paracrine secretion of growth factors and cytokines and the expres‐ sive effects of oxidized lipoproteins in particular. The distributional nature of disturbed blood flow is significant in the role of selective participation of injury to the overlying endothelial cells that become permeable to the inflow of lipoproteins within the vascular wall. Low density lipoproteins play a major role in initiating progressive atherosclerosis whereas high density

Hence, an overall series of dimensional agonists conform to and further establish the emer‐ gence of hypoxic influence in the quantitative formulation of the individual atherosclerotic plaque within a highly permissive micro-environment of vascular wall pathology. The sig‐ nificance of multi-component participation is symptomatic of the essential activation of en‐ dothelial cells that are at the interface with disturbed blood flow. Also, the accelerated or aggressive forms of atherogenesis seen in many forms of dyslipoproteinemias illustrate such

Directional proportions in redistribution of injury to the vascular wall are conceptually a

The murine models of atherosclerosis, particularly the transgenic models of absent ApoE gene and of absent low density lipoprotein receptor fed on a Western diet indicate the role played by lipoproteins as initiators and promoters of an essentially permissive micro-envi‐ ronment that is instrumental in atherogenesis as micro-environmental conditioning and preconditioning. In such manner, conditional remodelling of microenvironmental factors involves the characterization of many of the contributing agonists in atherogenesis. Hypoxia of the endothelium and intima is a central theme in such conditioning and allows for the multiple agonists in atherogenesis to contribute to the essential individualization of the pla‐ que within systemizing schemes of vascular wall atherosclerosis. Pathological angiogenesis enhances disease progression, increases macrophage infiltration and perpetuates necrosis

Cellular phenotype switches are a feature affecting particularly endothelial expression of ad‐ hesion molecules and the generation of secretory roles for smooth muscle cells. P-selectins and to a lesser extent E-selectins are significant participants in adhesion of leukocytes to par‐ ticular sites in the endothelium and allow for contributions also by vascular adhesion mole‐ cules and intercellular adhesion molecules and integrins. The matrix proteoglycans significantly accumulate as a result of such phenomena that promote chemotaxis of leuko‐

cytes from flowing blood and the drawing of smooth muscle cells into the intima.

tor-1 mitogenic effects [6].

244 Current Trends in Atherogenesis

**12. Self-progression**

and hypoxia [25].

lipoproteins suppress inflammation and thrombosis [1].

phenomenon within parametric contexts of endothelial cell dysfunction.

mechanism of a quantitatively self-progressive establishment in atherogenesis.

Incremental involvement of the intima corresponds to a progression that spatially conforms to effects of a disturbed blood flow that interacts with the endothelium. Dysfunctionality of endothelial cells arises within contexts of such interface phenomena in the realization of the quantitative attributes of increasing hypoxic injury and as dictated by the an accumulation of oxidized lipoprotein core.

Developmental parallels of involvement permit the destruction of the vascular intima that however promotes dimensions of aggregation of monocytes and the transformation to foam cells. In such manner, parameters of increasing involvement of the intima with atrophy of the tunica media progressively increases the abnormal flow of blood and promotes distur‐ bed reactivity of endothelial cells. It is such cyclical disturbance that increases also the sus‐ ceptibility to progressive accumulation of lipoprotein within the vascular wall.

A conceptual realization of developmental events is suggestive of a series of parallel path‐ ways that coincidentally progress as overlapping systems of attempted reconstitution of pathways of possible recovery in the face of incremental destruction of the vascular wall. Monocyte recruitment into the vessel wall is a rate-limiting step in atherogenesis with a crit‐ ical role played by reactive oxygen species [35].
