**4. Definition of vascular remodeling**

**3. Angiogenesis in the vessel wall**

**1.** atherosclerosis progression

vessels in pathological conditions.

**2.** plaque instability

An interesting question could be: How do the vessel wall progenitor cells migrate to the endothelial and intima layer of the vessel? The answer is the vasa vasorum. These play a significant role in transporting cells to the intimal region and have positively correlated with the development of atherosclerosis [35, 36]. In atherosclerotic lesions abundant microvessels can be

The real thing is that decreased blood supply through the adventitial vasa vasorum can trigger atherogenic intima thickening [37, 38]. Using the Lac-Z mice, Xu et al. [10] provided unique insights into the formation of these microvessels. It was clearly demonstrated that endothelial cells of microvessels within allografted vessels were derived from bone marrow progenitor cells (**Figure 1**). These results suggest a potentially dual role of EPCs in transplant atherosclerosis, protective through the repair of the denuded endothelium and promoting plaque

**Figure 1.** EPC origins. EPCs could be released from bone marrow, fat tissues, vessel wall, especially adventitia and spleen, liver, and intestine, where they form a circulating EPC pool. They can then contribute to the repair of damaged

observed. The vasa vasorum are considered to significantly contribute to:

**3.** also authors, support that contribute to plaque regression.

198 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

The vascular wall is formed by endothelium cells, smooth muscle cells, and fibroblasts interacting to form an autocrine-paracrine complex. During vascularization, the vascular wall cells detects changes in the environment, releasing communication signals as growth factors, inflammation mediators, and paracrine mediators that influences on vascular structure and function. The results are vascular remodeling. This is an active process of structural change that involves changes in at least four cellular processes: cell growth, cell apoptosis, cell migration, and the synthesis or degradation of extracellular matrix.

Vascular remodeling is dependent on dynamic interactions between: (1) local growth factors, (2) vasoactive substances, and (3) hemodynamic stimuli, and is an active process that occurs in response to long-standing changes in afterload conditions; that it may subsequently contribute to the pathophysiology of vascular diseases and circulatory disorders [39].

Increased peripheral vascular resistance in hypertension was uniformly ascribed to a higher volume of wall material per unit length of vessel or "hypertrophy." It was always thought that the process of vascular hypertrophy was only due to increased muscle cells, as in the left ventricle, the term remodeling was first applied to the resistance vessels by Baumbach and Heistad to indicate a structural rearrangement of existing wall material around a smaller lumen [39–41].

Mulvany proposed that vascular remodeling should encompass any change in diameter noted in a fully relaxed vessel, not explained by a change in transmural pressure or compliance, and therefore due to structural factors [42–44]. With the objective of to be operational, the classification necessitates appropriate methods for the measurement of resistance vessels dimensions, supplying factors either removed or controlled for: (i) vascular tone, (ii) transmural pressure, and (iii) vessel compliance [38, 45].

## **5. Classification of vascular remodeling**

Consideration of morphological changes has changed over time. Gibbons proposed a classification based on the response to increased blood pressure. These changes are displayed predominantly in media-to-lumen ratio (M/L), changing the vessel wall width for increased muscle mass (**Figure 2A**) or in the reorganization of cellular and noncellular elements (**Figure 2B**). These changes increase vascular reactivity, thus enhancing peripheral resistance. Another mechanism are mainly involves changes in the dimensions of the lumen (**Figure 2C** and **D**). In this case, the restructuring of the active components and cell signals does not

**Figure 2.** Changes are predominantly in media-to-lumen ratio (M/L), changing the vessel wall width for increased muscle mass (A) or in the reorganization of cellular and noncellular elements (B). Another mechanism of remodeling are mainly involves changes in the dimensions of the lumen (C) and (D). In this case, the restructuring of the active components and cell signals does not result in significant changes in the dimensions of the vascular lumen. Another form of vascular remodeling is microcirculation rarefaction (E) and (F).

result in significant changes in the dimensions of the vascular lumen; the changes in vessel wall thickness are relatively small. Clinical examples of this type of restructuring include the dilation of vascular remodeling associated with a constantly high blood flow (**Figure 2D**) (e.g. arteriovenous fistula) or the loss of cellularity and extracellular matrix proteolysis, resulting in the formation of an aneurysm. Equally, a reduction in the diameter of the vascular mass results from a long-term reduction in blood flow (**Figure 2C**). In fact, microcirculation rarefaction is another form of vascular remodeling that promotes hypertension and ischemic tissue. The vascular wall is also markedly changed in response to vascular injury (**Figure 2E** and **F**). In neointima, forms of reparative response to injury, as thrombosis, migration and vascular smooth muscle cells (VSMCs) proliferation, increased matrix production, and infiltration of inflammatory cells also exist.

Hypertension is associated with structural changes in the resistance vessels such as reduction in lumen diameter and increase in M/L ratio. This mode of structural change has been called "remodeling" [46].

Structural changes in resistance vessels are described as a rearrangement process to understand the pathogenesis of the disease and its therapeutic approach. However, it has been discussed that the term "remodeling" is not ideal because it is frequently used to describe any change in the structure of the vessel or myocardium. To avoid this difficulty, some authors make four proposals [47].

First, the term "remodeling" is limited to situations where there is a change in the lumen of a relaxed vessel, as measured under standard intravascular pressure. The changes in the characteristics of the wall material do not take into account the change in the vascular lumen.

Second, the process of changing the vessel wall without changes in the amount or characteristics of the materials are termed eutrophic remodeling. This process can be characteristic from situations involving an increase in the amount of material (hypertrophic remodeling) and those involving a reduction in the amount of material (hypotrophic remodeling).

Third, changes associated with decreased or an increased in lumen diameter should be classified as internal remodeling and external remodeling, respectively.

Finally, the remodeling process should be quantified. The term "remodeling index" refers to the variations of lumen referred to as eutrophic remodeling, depending on the changes in the wall section area.

The four proposals above allow for accurate terminology. Thus, the increase in the M/L ratio and decrease in the lumen diameter in resistance vessels of patients with essential hypertension without any change in the amount of wall material is called inner eutrophic remodeling. The decrease in the lumen diameter of the renal afferent arteriole with a decrease in the amount of wall material is called inner hypotrophic remodeling.

Chronic changes in hemodynamic forces structurally alter the vascular wall. In addition, hemodynamic changes are not the only production mechanisms of vascular remodeling. The inflammatory response and changes in the components of the matrix have been suggested as important mediators in the vascular adaptation process [48].

**Figure 3** highlights schematically the adaptation of these changes in different pathologies, including structural changes to the intima layer that contribute to remodeling of the vascular wall. Thus, outward remodeling compensates for atherosclerotic plaque growth and delays the progression of blood flow limitation during stenosis, whereas during restenosis, intimal hyperplasia causes a narrowing of the lumen.

result in significant changes in the dimensions of the vascular lumen; the changes in vessel wall thickness are relatively small. Clinical examples of this type of restructuring include the dilation of vascular remodeling associated with a constantly high blood flow (**Figure 2D**) (e.g. arteriovenous fistula) or the loss of cellularity and extracellular matrix proteolysis, resulting in the formation of an aneurysm. Equally, a reduction in the diameter of the vascular mass results from a long-term reduction in blood flow (**Figure 2C**). In fact, microcirculation rarefaction is another form of vascular remodeling that promotes hypertension and ischemic tissue. The vascular wall is also markedly changed in response to vascular injury (**Figure 2E** and **F**). In neointima, forms of reparative response to injury, as thrombosis, migration and vascular smooth muscle cells (VSMCs) proliferation, increased matrix production, and infiltration of

**Figure 2.** Changes are predominantly in media-to-lumen ratio (M/L), changing the vessel wall width for increased muscle mass (A) or in the reorganization of cellular and noncellular elements (B). Another mechanism of remodeling are mainly involves changes in the dimensions of the lumen (C) and (D). In this case, the restructuring of the active components and cell signals does not result in significant changes in the dimensions of the vascular lumen. Another form

Hypertension is associated with structural changes in the resistance vessels such as reduction in lumen diameter and increase in M/L ratio. This mode of structural change has been called

Structural changes in resistance vessels are described as a rearrangement process to understand the pathogenesis of the disease and its therapeutic approach. However, it has been discussed that the term "remodeling" is not ideal because it is frequently used to describe any change in the structure of the vessel or myocardium. To avoid this difficulty, some authors

First, the term "remodeling" is limited to situations where there is a change in the lumen of a relaxed vessel, as measured under standard intravascular pressure. The changes in the characteristics of the wall material do not take into account the change in the vascular lumen. Second, the process of changing the vessel wall without changes in the amount or characteristics of the materials are termed eutrophic remodeling. This process can be characteristic from

inflammatory cells also exist.

of vascular remodeling is microcirculation rarefaction (E) and (F).

200 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

"remodeling" [46].

make four proposals [47].

**Figure 3.** Schematic adaptation of changes in different pathologies, including structural changes to the intima layer that contribute to remodeling of the vascular wall. Thus, outward remodeling compensates for atherosclerotic plaque growth and delays the progression of blood flow limitation during stenosis, whereas during restenosis, intimal hyperplasia causes a narrowing of the lumen.

In summary, vascular wall remodeling is the result of changes in cellular and noncellular components, depending on the disease process causing the changes. Changes in the growth and migration of VSMC, endothelial dysfunction, inflammatory processes, and the synthesis or degradation of extracellular matrix components may be present during the disease process.
