**2.4. Initiation of atherosclerosis**

Fasting plasma insulin levels in a normal insulin-sensitive individual are usually in the lowpicomolar range (50–150 pM). At this range, insulin constitutively stimulates the PI3K pathway, which participates in the regulation of the metabolic effects of insulin and maintenance

In insulin-resistant states, such as obesity and diabetes, fasting insulin levels may reach the nanomolar range and are often associated with activation of RAAS. In addition, insulin stimu-

The spectrum of clinical and morphological changes that can be displayed has changed over time. One of the classifications we find is that proposed by author Gibbons [12]. These changes are shown predominantly in the relationship of light/medium vessel by changing the ratio of wall thickness by an increase in muscle mass or reorganization of the cellular and noncellular components. These changes increase vascular reactivity, which promotes increased peripheral resistance in diseases such as hypertension. Another form of vascular remodeling involves primarily changes in the dimensions of the light. In this example, the restructuring of the active components of cellular and noncellular vascular wall results in significant changes in the dimensions of the vascular lumen, with relatively small changes in wall thickness. The clinical examples of this type include remodeling associated with vascular dilation of blood flow which is consistently high, for example, an arteriovenous fistula or loss in cellularity and proteolysis of extracellular matrix, resulting in the formation of an aneurysm. By contrast, a mass reduction vascular caliber results from a long-term reduction in blood flow. In fact, rarefaction of the microcirculation is another form of vascular remodeling. The architecture of the vascular wall is also markedly changed in response to vascular injury. Neointima is formed as part of a repair response to injury involving thrombosis, migration, and prolifera-

tion of vascular cells, production of the matrix, and infiltration of inflammatory cells.

The term "remodeling" is limited to situations in which there is a change in the lumen of a vessel relaxed, measured under a standard intravascular pressure, and where changes in the characteristics of the wall material (i.e., the wall stiffness) do not consider the change in the vascular

Chronic changes in hemodynamic forces produce structural alterations in the vascular wall, as stated above. Furthermore, hemodynamic changes are not the only production mechanisms of vascular remodeling [14], and the role of the inflammatory response and changes in matrix components have been suggested as mediators in this process of vascular adaptation [15].

To complete the above concept, the vascular wall remodeling is the result of changes in cellular and noncellular components, depending on the disease process causing the changes. Changes in growth and migration of VSMC, endothelial dysfunction, the inflammatory process, synthesis, or degradation of extracellular matrix components may be present in this process.

The traditional view of atherosclerosis as a lipid storage disease crumbles in front of the large and growing evidence that inflammation contributes to the center at all stages of the

of vascular tone [11].

80 Ultimate Guide to Insulin

**2.2. Vascular changes**

lumen [13].

**2.3. Vascular remodeling and inflammation**

lation of the PI3K pathway is selectively impaired.

It has been shown that atherosclerosis is not only a disease of lipid deposition but also a complex interaction between resident cells, inflammatory cells, and extracellular matrix, associated with a characteristic phenotypic change of macrophages to foam cells.

A key part of this interaction between the endothelium and the leukocytes is the vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 binds to monocytes and T lymphocytes; these leukocytes are found in early atherosclerotic plaques. The most important stimuli for the membrane docking of this molecule are the nuclear factor kB (NF-kB) as well as the interleukin-1β (IL-1β) and the tumor necrosis factor (TNF-α) [10].

Cell adhesion molecules (CAM) are essential in the mediation of adhesion and transendothelial migration of leukocytes. In several murine models, the absence of CAM reduces atherogenesis [17]. We have demonstrated the presence of VCAM-1 in the endothelium in an experimental model of metabolic syndrome, in which the expression of this protein is familiar with the AT1 receptor (AT1R) and the local inflammatory process. High levels of ICAM-1 are predictive of cardiac events and are also independent cardiovascular risk factors [18]. This relationship was examined by Pradhan et al. [19], who showed that men with and without prior ischemic heart disease, accelerated atherogenesis, are associated with elevated levels of ICAM-1.

VCAM-1 is expressed in endothelial cells at sites predisposed to plaque formation [20]. By contrast, ICAM-1 is expressed throughout the plate; VCAM-1 is detected only in areas of rupture. In addition, VCAM-1 levels have a consistent association with atherosclerosis; high levels of VCAM-1 in the transcardiac gradient correlate with endothelial dysfunction and the progression of coronary atherosclerosis [21].
