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Gelatinases MMP-2 and MMP-9: Comparison
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Please note this is a comparison between Version 1 by Asparuh Nikolov and Version 2 by Vicky Zhou.

Gelatinases (matrix metalloproteinase-2 and -9) are enzymes from the matrix metalloproteinases (MMPs) family, which are associated with collagen degradation. MMP-2 is capable of cleaving gelatine, types I and IV collagens, while MMP-9 is incapable of direct proteolysis of collagen I and digests collagen type IV. MMP-2 and -9 are both important regulators of vascular and uterine remodeling in a healthy pregnancy. Alterations in the collagen structure of the uterus and spiral arteries are observed in women with hypertensive disorders of pregnancy. Dysregulation of MMP-2 and MMP-9 has been implicated in abnormal vasodilation, placentation, and uterine expansion in preeclampsia. Early preeclampsia detection is paramount for risk stratification and prevention of further complications. Understanding the role of MMP-2 and-9 in uteroplacental and vascular remodeling could help design new approaches for prediction and management of preeclampsia.

  • extracellular matrix
  • spiral arteries
  • collagen types I and IV
  • microcirculatory ischemia
  • biomarkers
  • preeclampsia

1. Introduction

The MMPs are a group of more than 25 Zn

2+

-requiring endopeptidases with overlapping activities against a variety of ECM components

[1][2]

. They are proteolytic enzymes with common functional domains and an action mechanism associated with the degradation of ECM components. MMPs are proteases that are zinc dependent and they can be activated by various types of cytokines and growth factors

[3]

. One of the most decisive properties of metalloproteinases is their ability to bind to components of the extracellular matrix and, in particular, to collagen and elastin. Activated macrophages in the wall of arterial vessels secrete MMPs. From the perspective of normal and pathological physiology, the capacity of MMPs to change tissues is crucial. On the basis of the current data, MMPs are classified into groups according to the type of proteolytic substrate (extracellular matrix component) against which they act and degrade, respectively. These groups are as follows: collagenases (MMP-1 and MMP-13), gelatinases (MMP-2 and MMP-9), stromelysins such as MMP-3, and membrane MMPs

[4]

.

MMP-2 and MMP-9 play a central role in endometrial tissue remodeling during a healthy pregnancy, because they are able to degrade components of the ECM. MMP-2 and MMP-9 are frequently implicated as important factors that contribute to the cytotrophoblast invasion into the maternal vasculature. This assumes that MMP-2 and MMP-9 are implicated in the remodeling of placental and uterine artery. It has been postulated that MMP-2 and MMP-9 play a crucial role during pregnancy, being involved in the degradation of collagen I and IV, thus, implementing a central part in endometrial tissue remodeling during pregnancy. Therefore, MMP-2 and MMP-9 are regarded to be the key enzymes during implantation. The control of expression and regulation of MMPs and their inhibitors plays an important role in healthy and complicated pregnancies. There is increasing evidence that dysregulation of MMP-2 and -9 has been associated with PE.

Gelatinases (MMP-2 and MMP-9) easily digest gelatin. This process is favored by their three fibronectin type II repeats that bind to gelatin/collagen. Different ECM molecules are also digested, including types IV, V, and XI collagens; laminin; aggrecan core protein; etc. Similar to collagenases, MMP-2, but not MMP-9, digests collagens I, II, and III [5][6]. The collagenolytic activity of MMP-2 in solution is much weaker than MMP-1, however, since “proMMP-2 is recruited to the cell surface and activated by the membrane-bound MT-MMPs, it may express reasonable collagenolytic activity on or near the cell surface” [7].

1.1. MMP-2 Structure and Function

MMP-2 (gelatinase A, type IV collagenase) is one of the two discovered human gelatinases that are named for their ability to degrade gelatin (denatured collagen) proteolytically. “MMP-2 is ubiquitously expressed as a 72-kDa proenzyme and subject to extensive glycosylation” [8]. In contrast to MMP-9, MMP-2 expression is constitutive and most proinflammatory stimuli fail to raise the degree of expression, because the gene lacks binding sites for proinflammatory transcription factors such as activator protein-1 [9]. The activation status of MMP-2 is crucial for its function in angiogenesis.

The catalytic domain, containing cysteine-rich inserts resembling collagen-binding regions of the type II repeats in fibronectin, is a feature that distinguishes MMP-2 from other MMPs. Binding and cleavage of collagen and elastin need these inserts [10]. MMP-2 is capable of cleaving gelatin; types I, IV, and V collagens; elastin; and vitronectin [11]. Gelatinases degrade collagen in the vascular basal membranes. MMP-2 can also facilitate cell migration by direct degradation of the basement membrane allowing neutrophils and lymphocytes to infiltrate, or releasing chemoattractants, for example, [12]. MMP-2 is involved in both activating and inhibiting inflammation by releasing proinflammatory mediators, such as the active form of interleukin-1β and proteolytic degradation of chemoattractants.

1.2. MMP-9 Structure and Function

MMP-9 (gelatinase B, type IV collagenase) was firstly detected in neutrophils in 1974 [13]. “MMP-9 is expressed in the form of 92-kDa proenzyme, which can be activated to the 83-kDa mature enzyme” [14]. Noteworthy, the activation of MMP-9 can be mediated by removal of the prodomain by serine proteases or other MMPs [15]. An alternative pathway can be a direct response to oxidative stress that disrupts the cysteine switch [16].

MMP-9 is incapable of direct proteolysis of collagen I [11]. Collagen types IV, V, VII, X, and XIV; fibronectin; and laminin have been reported to be digested by MMP-9 [17]. The biologically active form of vascular endothelial growth factor (VEGF) is released by MMP-9, thus, playing a key role in angiogenesis. The direct proteolytic degradation of vascular basement membrane proteins complements this process, demonstrating that MMP-9 (even more than MMP-2) could play an important role in the formation of new blood vessels. It has been found that in a xenograft model, the hemopexin domain of MMP-9 was an inhibiting factor in angiogenesis, as demonstrated by decreased invasion of glioblastoma cells overexpressing the MMP-9 hemopexin domain [18].

MMP-9 plays important roles in physiological processes such as reproduction, growth, and development [19][20]. The functions of MMP-9 in angiogenesis are exerted in physiological, as well as pathological conditions, for example, premature rupture of membranes [21][22][23]. MMP-9 is able to process cytokines and chemokines similar to MMP-2. It has been postulated that MMP-9 cleaves interleukin-8 to its more potent truncated form, activates IL-1b, and transforms growth factor beta [11]. MMP-2 is known to be mainly inhibited by TIMP-2, while MMP-9 is primarily inhibited by TIMP-1 [24]. Universally, MMP-2 is expressed under physiological conditions, while MMP-9 is present only constitutively in neutrophils, where it is stored in granules to be released quickly after stimulation [25]. In many other cell types, the expression is inducible by (inflammatory) stimuli [26], increased malignant cell lines, and correlates with their metastatic potential [27]. As previously mentioned, MMP-9 was first discovered in neutrophils, whereas proMMP9 is TIMP-free in neutrophils [13]. Neutrophil-derived MMP-9 is distinguishable from other sources, since it forms a covalent complex with neutrophil gelatinase B-associated lipocalin (NGAL) [28].

Collagen is the main structural component of connective tissue. Matrix metalloproteinases are responsible for breaking down collagen and other extracellular matrix proteins. In physiological conditions, MMPs are released into the extracellular space, thus, degrading the ECM and favoring tissue remodeling and repair. MMP-2 and MMP-9 are known to cleave various other substrates other than ECM proteins and they have multiple unique substrates, but the focus of our review is on MMP-2 and -9 being ECM degraders.

2. Types I and IV Collagen Turnover in Healthy Pregnancy

Normal placental vascularization is a cornerstone of a healthy pregnancy. Uterine spiral arteries transform physiologically to ensure sufficient blood and nutrient supply to the fetus. The spiral arteries’ main function is to supply the placenta. Hereby, in a healthy pregnancy, they are modified for uteroplacental blood flow. This process involves loss of smooth muscle and the elastic lamina from the vessel wall as far as the inner third of the myometrium and is associated with a five- to ten-fold dilation at the vessel mouth. During early pregnancy, the placenta plays an important role as a maternal-fetal interface through several processes including vasculogenesis, angiogenesis, trophoblast invasion, and vascular remodeling [29]. Failure of the physiological conversion of the spiral arteries can cause a number of complications, including intrauterine growth restriction and preeclampsia [30]. MMPs and their inhibitors are known to play a crucial role in trophoblast invasion into the uterine wall [31]. MMPs play an important function in the profound changes involving the microarchitecture of the uterus. These changes are required for spiral vessels’ transformation and create an optimum environment for embryonic development, thus, involving a grounding transformation [32]. The blastocyst is known to attach to the uterine wall. This process leads to a complex dialogue between membrane ligands and receptors that penetrate the epithelium and cross the basal lamina [33]. The invasion of trophoblast cell is strictly regulated by signaling events, autocrine and paracrine stimulus, specific protein recognition, and immunological tolerance, promoting MMPs and inhibiting factors TIMPs [34]. It can be accented that MMP-2 and -9 are associated with ECM remodeling and trophoblast invasion of the spiral arteries in both healthy and complicated pregnancy.

The major structural proteins in the uterine wall have been found to be collagen types I and III. When the uterus expands during a pregnancy, collagen turnover intensifies. The connective tissue proteins COL1 and COL4 are essential for structural stabilization and control of cell growth and differentiation. Collagen types I and III synthesis and degradation in the human uterine ECM are dynamic processes that reflect a healthy and complicated pregnancy. In order to provide expansion of the growing uterine content, regulated collagenolysis and/or changes in collagen cross-linking is required. Type IV collagen is uniquely present in basement membranes of spiral arteries (the most distal part of uterine arterial vasculature) and represents their predominant structural element [35][36]. In a healthy pregnancy, uterine spiral arteries undergo physiological structural and functional changes to supply the fetus with blood and nutrients.

As previously mentioned, MMP-2 and MMP-9 are important regulators of uterine and vascular remodeling. A normal pregnancy is associated with extensive uterine and spiral arteries remodeling and proteolysis of extracellular matrix, mediated by matrix metalloproteinases (MMPs) [37]. Furthermore, remodeling of cervical tissue is known to be significant, with decreased concentrations of collagen and proteoglycans concomitant with increased collagenolytic activity [38][39].

3. Conclusions

Dysregulation interplay between MMP-2, -9, and their natural tissue inhibitors TIMP-2 and -1 might be one of the possible causes for pathological collagen types I and IV turnover in preeclampsia. The disturbed metabolism of the abovementioned fibrillar connective tissue proteins could partially explain the uterine ECM changes, manifested as altered structure of uterus and abnormal spiral arteries remodeling in women with preeclampsia. In conclusion, matrix metalloproteinases -2 and -9 have promising potential as biomarkers and might be useful in the diagnosis, prognosis, and monitoring of the development of preeclampsia.

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