Molecular Determinants of Chronic Venous Disease: History
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Contributor:
Davide Costa
,
Michele Andreucci
,
Nicola Ielapi
,
Giuseppe Filiberto Serraino
,
Pasquale Mastroroberto
,
Umberto Marcello Bracale
,
Raffaele Serra

Chronic Venous Disease (CVD) refers to several pathological and hemodynamic alterations of the veins of lower limbs causing a wide range of symptoms and signs with a high prevalence in the general population and with disabling consequences in the most severe forms. The etiology and pathophysiology of CVD is complex and multifactorial, involving genetic, proteomic, and cellular mechanisms that result in changes to the venous structure and functions. Expressions of several genes associated with angiogenesis, vascular development, and the regulation of veins are responsible for the susceptibility to CVD. Evidence shows that several extracellular matrix alterations (ECM) could be identified and in some cases pharmacologically targeted. 

  • chronic venous disease
  • varicose veins
  • chronic venous leg ulcers
  • genetics
  • extracellular matrix
  • histopathology

1. Introduction

Chronic Venous Disease (CVD) refers to pathological and hemodynamic alterations of the veins of lower limbs that cause a wide range of symptoms and signs, ranging from mild clinical manifestations such as telangiectasia, reticular veins, and varicose veins (VV) to more severe forms such as skin changes and chronic venous leg ulcers (CVLUs). CVD has a prevalence of up to 57% and 77% in men and women, respectively, in the adult general population, considering the presence of any related clinical manifestation in affected patients [1][2].
In particular, CVD clinical manifestations are described by the clinical, etiological, anatomical, and pathophysiological (CEAP) classification, which defines the following clinical classes: C0 includes no visible or palpable signs of venous disease; C1 includes telangiectasia and reticular veins; C2 includes trunk VV of variable origin; C2r includes recurrent varicose veins; C3 includes lower limbs edema; C4a includes pigmentation or eczema; C4b includes lipodermatosclerosis or atrophie blanche; C4c includes corona phlebectatica; C5 includes healed ulcer; C6 includes active ulcer; and C6r includes recurrent active ulcer. [3] The most severe form of CVD is defined as Chronic Venous Insufficiency (CVI) and corresponds to the C3–C6 classes of CEAP [1][2].
The explicit mechanisms of CVD are not well understood, but it seems that genetics and several proteomic alterations play an important role in the susceptibility, development, and progression of CVD [4].
The current treatment of CVD may be medical and/or physical and/or surgical, but none of them could be considered definitely effective for patients suffering from CVD. Despite best surgical or endovascular care, recurrence following vein surgery is more than 20%, and about 25–50% of CVLUs remain unhealed after six months of adequate treatment [5][6][7]. Hence, in this area, the current interest of Precision Medicine (PM) for molecular determinants of CVD has increased in order to find molecules that could help to predict this disease and its complications and to better tailor treatment strategies and the related follow-up of patients [8][9][10].

2. The Genetic Influence

More than 60% of patients with CVD have a clear association among family members; thus, a clear genetic influence exists behind the pathogenesis of CVD [11]. In particular, Cornu-Thenard et al. studied 134 families and found that 90% of children will develop CVD when both parents suffer from this disease, compared with 25% of males and 62% of females when one parent suffers from CVD, and with 20% when neither parent is affected [12].
There are several approaches that have been used to study the genetic influence in CVD. These include heritability analysis through family studies, differential gene expression analysis, and genomic variation studies, either by comparing individual candidate genes or casting the search more widely, with genome wide association studies (GWAS). [13]. The pathogenesis of CVD is a very complex multifactorial process, and even a single gene effect can cause little effective influence, and the impact of a particular polymorphism will depend also on genotype–environment interactions, considering also epigenetic mechanisms, which may even be specific to single patients’ pathophysiology [14].
The expression of several genes associated with angiogenesis, vascular development, and the regulation of vein wall homoeostasis is altered in CVD [15][16].
Considering angiogenesis and vascular development abnormalities, there is robust evidence for a specific role of some genes such as forkhead box protein C2 (FOXC2) gene and vascular endothelial growth factor A (VEGFA) gene [15].
The FOXC2 gene, located on chromosome 16q24, encodes a transcription factor that regulates the expression of genes involved in the normal development of the venous and lymphatic systems. In particular, it is required during the early maturation and formation of venous and lymphatic valves [15][17][18][19][20][21]. Moreover, evidence indicates that FOXC2 overexpression in venous endothelial cells (ECs) may upregulate the expression of Delta Notch pathway-related proteins such as Notch-1 and its ligand delta-like-4 (Dll4) and Hey2, which plays a key role in the development of vascular networks [22][23]. The molecular alterations in Dll4–Hey2 signaling seem also to be associated with smooth muscle cell hypertrophy and hyperplasia in varicose veins [24]. Foxc2 transcription factor also has a role in regulating angiogenesis via the induction of integrin β3 expression. Integrin β3 is a cell adhesion receptor that interacts mainly with extracellular matrix (ECM) components such as fibronectin and vitronectin [25]. Foxc2 transcription factor may also affect the function of CXC chemokine ligand 12 (CXCL12) and its receptor, CXCR4, which are critical for the process of angiogenesis in the vascular system [26].
Several clinical studies have found that mutations in FOXC2 gene, as well as specific single-nucleotide polymorphisms (SNPs), are strongly associated with CVD [17][27][28][29][30][31].
VEGFA gene encodes for vascular endothelial growth factor A (VEGF-A) protein, which is both a critical regulator of angiogenesis and a pivotal factor that is able to maintain the integrity and the functionality of the vessel wall [15][32]. VEGF-A mediates the growth of new blood vessels from pre-existing vessels (angiogenesis) by binding to the cell surface receptors VEGFR1 and VEGFR2, two tyrosine kinases located in ECs of the circulatory system. Increased expression of VEGF-A seems to determine a significant role in CVD pathogenesis as it is able to increases venous wall permeability determining edema and to decrease the tone of the vein wall, which may lead to vein dilation with blood stasis in the lower extremities’ vein system and subsequent venous hypertension development. Moreover, increased expression of VEGF-A may affect ECM remodeling through the imbalance of several proteolytic enzyme synthesis processes such as Matrix Metalloproteinases (MMPs) [33].
The activity of MMPs in ECM is controlled by specific tissue inhibitor of metalloproteinases (TIMPs) in order to maintain the homeostasis and the balance of ECM that supports the integrity of the vessel wall. The expression of several MMPs is increased in patients with CVD. The main cause of this increase is an imbalance between the activities of MMPs and TIMPs, resulting in the breakdown of ECM homeostasis in the vein wall [15]. In particular, Kunt et al. investigated the relationship between MMP-9 and TIMP-2 gene polymorphisms and CVD risk and showed that individuals with the C allele -418G for TIMP-2 were significantly associated with risk of CVD, whereas the individuals with GG genotype had a lower risk for CVD. They did not find statistically significantly difference between the patients with CVD and healthy controls for MMP9 gene analysis [34]. On the other hand, Xu et al. found that the -1562C/T allele in MMP9 is a risk factor for CVD and that the TIMP2 gene polymorphism -418G/C was also associated with CVD [35][36].
Iron overload has been implicated in the pathogenesis of CVD, and in particular HFE gene polymorphisms seem to be linked to developing the diseases and also to accelerating the progression to CVLU formation [15][37]. Specifically, C282Y mutation is responsible for an increase in the risk of CVLU by almost seven times [36]. In fact, it is documented that there is an elevated serum concentration of iron in CVD patients compared with healthy controls [15][37][38][39]. Furthermore, iron overload may serve as a further mechanism for MMP hyperexpression leading to CVLU [40].
Abnormalities in the genes encoding enzymes that control homocysteine metabolism, such as Methylenetetrahydrofolate reductase (MTHFR) gene, have been shown to predispose to CVD development [15]. In particular, Wilmanns et al. showed a strong influence of genotypes at MTHFR c.677C>T and c.1298A>C on the morphological specification of CVD and progression towards complicated disease (CEAP classes C3–C6) [41].

3. The Hormonal Influence

Sex hormones play a predominant role in CVD onset and pathophysiology, especially considering the influence of gender in this disease (predominance in women). In fact, some studies demonstrate that VVs are associated with increased estrogen receptors (ERs) and progesterone receptors (PRs) expression and with decreased androgen receptors (ARs) expression in all tunica layers of the vein wall [42][43]. Moreover, the expressions of ERs, in particular ERα, ERβ, and G protein-coupled ER (GPER), seem to correlate with the severity of CVD and with the clinical stage of the disease [42].
From a mechanistic point of view, ERs act by ER-mediated enhanced venous relaxation and decreased venous contraction, causing more distensible veins. In addition, progesterone inhibits vascular smooth muscles (VSMCs) contraction. The effect is more evident in women, as the estrogen levels are more elevated than in men; nevertheless, the same mechanism is also related to men [42][43][44][45][46].
Moreover, estrogens can induce the migration of VSMCs and induce CVD, also stimulating the promotion of MMP-2 and MMP-9 expression through the classical pathway of ERs [47].
The role of sex hormones could also explain, in part, the significant and statistically strong association between pregnancy and the development of VV during or after this time, according also with the number of pregnancies [48].

4. ECM Imbalance and Histopathology of CVD

Several pieces of evidence suggest that the development of CVD is secondary to defects in ECM components, determining weakness and altered venous function with warped valves, a thin vein wall, and subsequent dilated veins. In fact, the ECM provides a structural framework of a wide range of proteins such as collagen, proteoglycans, elastin, glycoproteins, and fibronectin in which various cellular components are embedded. The ECM is a dynamic system that maintains the integrity and homoeostasis of the vein through interactions with cellular components such as the endothelium and VSMCs [16].
Homoeostasis of the ECM is regulated by a group of enzymes called metalloproteinases (MPs) and TIMPs. There are several families of MPs, such as MMPs, ADAMs (a disintegrin and metalloproteinases), and ADAMTSs (a disintegrin and metalloproteinases with thrombospondin motifs). Specifically, MMPs are a group of several multi-domain zinc-dependent enzymes that have the ability to influence the migration, proliferation, and apoptosis of VSMCs, ECs, and inflammatory cells; ADAMs are a family of transmembrane and secreted proteins that have functions in cell adhesion and the proteolytic processing of the ectodomains of diverse cell surface receptors and signaling molecules; ADAMTSs descend from the ADAMs, but they have diverse functions and major roles, including the maturation of proproteins such as procollagen and ECM remodeling during morphogenesis. MMP-1, MMP-8, ADAM-17, and ADAMTS-4 appear to be primarily involved with chronic or irreversible complications of CVD such as CVLU. ADAMTS-1 and ADAMTS-7 were found to be elevated in all stages of CVD with respect to the healthy subjects. ADAMTS-5, TIMP-1, and TIMP-2 seem to be negatively associated with the progression of the disease and decrease progressively during the worsening of CVD. MMP-9, especially if complexed to neutrophil gelatinase-associated lipocalin (NGAL), is found to be elevated in all stages of CVD and in particular in more severe cases. NGAL is a protein belonging to the lipocalin family, with the ability to positively modulate the activities of MMP-9, protecting MMP-9 from the proteolytic degradation of TIMPs [49][50][51][52][53]. Moreover, MMP-2 seems also to have the effect of increasing vein wall tension with subsequent venous relaxation [54].
Furthermore, the regulation of the MPs is complex and occurs at different levels, including at gene transcription, protein translation, pro-MP activation, and endogenous inhibition by plasma proteins such as α2-macroglobulin and TIMPs, and thus it is not simple to identify the specific cause of alteration [16].
Interestingly, some evidence has showed that MP alterations could be druggable and that the assumption of some non-selective antagonist of MPs, such as tetracyclines, could results in reducing the time of wound healing in CVLU [55][56].
From a histopathological point of view, the degradation of ECM, due to MPs imbalance, is likely to contribute to the weakening and dilation of the vein vessel wall. In fact, the disruption of the elastic fibers, including fragmentation of the elastic laminas, and the thickening of individual collagen fibers, as well as the imbalance of elastin and collagen content have been found in VV. Furthermore, several changes in the cellular and ECM structure have been identified in all the layers of the vein wall in VV. VSMCs proliferate and infiltrate underneath the endothelial cell (EC) lining, leading to irregular intimal hyperplasia with associated collagen deposits [16][57]. These changes in VSMCs are mainly due to an imbalance between apoptosis and cell proliferation determining irregular proliferation patterns, probably mediated also by anomalous chemical signals such as those coming from inflammatory cytokines that can also be triggered by MPs [49][58] and also from transforming growth factor beta 1 (TGF-β1), a protein that is present in several cells of the cardiovascular system, such as ECs, VSMCs, myofibroblasts, and macrophages and is also a key regulator of ECM synthesis and remodeling. TGF-β1, in advanced stages of CVD, such as skin changes and lipodermatosclerosis (C4a and C4b clinical classes of CEAP), seems to induce a significant dermal fibroblast proliferative response with a subsequent progressive dermal fibrosis, typical of the aforementioned clinical classes of CVD [59].
Moreover, a recent study that evaluated samples obtained from VVs found a decreased vein innervation, and this may also account for the decreased venous contraction capacity of VSMCs, determining also the warping and the separation of valve cusps triggering the venous reflux. Other findings were VEGF-positive structures with an increasing trend in relation to the staging of the disease, and a decreasing expression of protein gene product 9.5 (PGP 9.5) in relation to the staging of the disease. PGP 9.5 is a neuroendocrine cell-specific protein related to vein innervation. Numerous amounts of fibronectin in VVs were found below the endothelial lining, and this accounts for a response to inflammatory processes in damaged veins. MMP-9 structures were also found with increasing trends in relation to the disease staging [60].
Furthermore, other histopathologic alterations have been documented in VVs such as focal intimal discontinuity and the denudation of endothelium, probably due to hypoxic damage to the ECs [61].
The ECM alteration determined by MP imbalance may also have a systemic localization involving other human structures characterized by collagen and elastin metabolism. In particular, the contemporary presence was documented, in selected patient populations, of multiple collagen-related disorders such varicocele, inguinal hernia, and VVs that had also MMP-9 abnormalities at tissue and plasma evaluation in common, confirming that CVD may be related to a more general and progressive disorder of collagen metabolism [62][63].

This entry is adapted from the peer-reviewed paper 10.3390/ijms24031928

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