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Longitudinal distribution of cytoskeletal markers within myometrium, basal endometrium and inner functional endometrium in the proliferative phase of the cycle. ( A ) α -sm actin is expressed in myometrial smooth muscle cells, myometrial vascular smooth muscle, stromal cells of the basal endometrium (small arrows) and the vascular smooth muscle cells of both basal and super fi cial functional endometrium (large arrows). ( B ) Sm myosin is present in the myometrial smooth muscle (arrow) and extends into the smaller calibre vessels of the super fi cial functional endometrium. It is more widely distributed within the vascular tree than γ -sm muscle actin. Unlike α -sm actin, myosin is not expressed in the stromal cells of the basal endometrium. ( C ) γ -sm actin is more restricted than the α - isoform. It is absent from the stromal cells of the basal layer and is not expressed in smaller calibre vessels (arrows). ( D ) Vimentin is weakly expressed in myometrial smooth muscle cells and is widely distributed in the endometrium. It is present in the glandular epithelium, stroma and vascular smooth muscle. Bar ϭ 110 μ m.
Source publication
Angiogenesis within the human endometrium involves the development of arterioles and elaboration of a capillary network. It was postulated that maturation of these arterioles involves a spatially regulated process of vascular smooth muscle cell (VSMC) differentiation. The endometrial vascular tree was therefore examined immunohistochemically for ev...
Contexts in source publication
Context 1
... vascular distribution of γ-sm actin was more basally than CD31 under the experimental conditions used. CD34 was found in endothelial cells throughout the vascular tree in restricted than either α-sm actin or sm myosin ( Figures 1C, 2C and 3C). Although patchy in the outer vessel wall, the γ endometrium and myometrium and was also expressed in endometrial stromal cells of the basal endometrium during the isoform was present throughout the entire thickness of the wall in basal vessels in the proliferative phase and was weakly secretory and menstrual phases of the cycle. ...
Context 2
... expressed in muscularized vessels which were surrounded by decidualized stroma. γ-sm actin was absent from smaller myometrium, CD34 reactivity was limited to perivascular stromal cells and spindle-shaped cells surrounding muscle muscularized vessels and capillaries throughout the stroma ( Figures 1C and 2C). cell bundles. ...
Context 3
... and progesterone receptor distribution was examined The spatial distribution of cytoskeletal markers within endo- within the walls of large muscularized vessels where it was metrial blood vessels possible to compare the distribution of smooth muscle markers in consecutive or semi-consecutive sections (Figure 4). Neither Three cytoskeletal proteins, α-and γ-sm actin and sm myosin, exhibited spatially distinctive patterns of expression within the of the receptors was found in VSMC or endothelial cells of endometrium and myometrium by the methods employed in endometrial vascular tree (Figures 1, 2 and 3). expressed in the stroma and glands comparable to the proliferat- ive phase of the cycle. ...
Context 4
... DNA binding protein may be involved in transcriptional activation during muscle endothelial tubes appears to be influenced by factors that promote cell migration, proliferation and differentiation. TGF- differentiation and may be important in maintaining the expres- sion of smooth muscle specific genes in the developing vessel α, which may be in this category, has been shown to promote the in-vitro smooth muscle differentiation of multipotent (Landerholm et al., 1999). ...
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The expression of collagen type VI in the extracellular matrix of rat uterine endometrial stroma after a decidual stimulus was examined by immunolocalization and immunoblotting. The intermediate filament protein, desmin, was used as a marker to identify decidual cells. Tissue was examined from pregnant animals and from ovariectomized, hormone-treat...
Puerarin, a selective oestrogen receptor modulator, intercepts implantation in rats, albeit at unacceptably higher doses. We developed poly lactic-co-glycolic acid-encapsulated nano-puerarin (PN) and mapped the molecular pathway underlying its anti-implantation effects. Smooth-surfaced and spherical PN having a mean diameter of ~147 nm was obtained...
Citations
... Under the influence of ovarian hormones, EPCs acquire an improved angiogenic potential, and P4-mediated PR improves the proliferative ability of EPCs in a dose-dependent manner [102]. Vessel remodeling, a type of endometrial neovascularization characterized by a high average microvessel length and low blood vessel junction, is prominent from the late proliferative to mid-secretory phase [103], accompanied by the proliferation of vascular smooth muscle cells and coverage of mural cells, which contribute to the maturation of endometrial vascular tissues [104][105][106]. A study reported that vessel maturation is primarily related to P4 while E2 has no impact on this process, implying that P4 rather than E2 plays a pivotal role in this process [26]. ...
Ovarian sex steroids can modulate new vessel formation and development, and the clarification of the underlying mechanism will provide insight into neovascularization-related physiological changes and pathological conditions. Unlike estrogen, which mainly promotes neovascularization through activating classic post-receptor signaling pathways, progesterone (P4) regulates a variety of downstream factors with angiogenic or antiangiogenic effects, exerting various influences on neovascularization. Furthermore, diverse progestins, the synthetic progesterone receptor (PR) agonists structurally related to P4, have been used in numerous studies, which could contribute to unequal actions. As a result, there have been many conflicting observations in the past, making it difficult for researchers to define the exact role of progestogens (PR agonists including naturally occurring P4 and synthetic progestins). This review summarizes available evidence for progestogen-mediated neovascularization under physiological and pathological circumstances, and attempts to elaborate their functional characteristics and regulatory patterns from a comprehensive perspective.
... Smooth muscle and pericytes are reduced in the superficial layer of the endometrium, and the most superficial vessels consist only of endothelial cells. 39 In the secretory phase, the growth of the subepithelial capillary plexus takes place and endothelial cells maintain a marked CXCR7 staining. Endometriosis implants are typically characterized by glandular epithelium and stroma surrounded by abundant vascularization (as a result of neoangiogenesis) and myofibroblasts. ...
Endometriosis is a chronic inflammatory disease. Dysfunctional regulation of chemokines and chemokine receptors is a crucial aspect of endometriosis pathogenesis. Chemokine G-protein-coupled receptors (GPCRs) are important drug targets that regulate inflammation and immunity. Recently, CXCR7, a C-X-C motif containing GPCR, has been identified as a receptor for chemokine ligand CXCL12, one of the best characterized chemokines for cell trafficking, angiogenesis, and cell proliferation in cancer and inflammation. Here, we investigated the expression and localization of CXCR7 in human endometriosis and a murine model of the disease. Normal endometrial epithelium and stroma showed undetectable or very low expression of CXCR7, without any significant changes across phases of the menstrual cycle in humans. CXCR7 is significantly upregulated in endometriosis, showing higher staining in glands and in associated vessels. The mouse model recapitulated the human findings. In conclusion, overexpression of CXCR7 in different cellular populations of endometriosis microenvironment may play a role in the pathogenesis and represent a novel target for treatment.
... This suggests that exposure to progestogens may be associated with the acquisition of a myofi broblastic phenotype by endometrial stromal cells. This seems to support the observation by Kohnen et al. (2000) that some stromal cells in the basal endometrium express α-smooth muscle actin and thus exhibit a myofi broblastic phenotype in respose to progestogens [ 54 ]. Leppert and Yu (1991) used scanning electron microscopy and reported that the extracellular matrix of the myometrium contains fl at sheets or lamellae within a spongelike matrix [ 55 ]. ...
This useful book examines the full spectrum of data available on uterine adenomyosis, covering early to modern literature. The authors look at the recent scientific advancements in the pathophysiology of this disease, giving the reader insight into its diagnosis before hysterectomy and its clinical impact on fertility.
Uterine Adenomyosis is an in-depth resource guide for the practicing gynecologist, post-graduate researcher and any medical professional or scientist seeking to broaden their understanding of adenomyosis.
... Previous studies investigated VSMC characteristics in the endometrium of normal cycling and LAPC-treated women (21)(22)(23). As an early differentiation marker, αSMA is expressed by VSMCs of endometrial vessels, by pericytes attached to capillaries, and by stromal myofibroblasts (21,22). ...
... Previous studies investigated VSMC characteristics in the endometrium of normal cycling and LAPC-treated women (21)(22)(23). As an early differentiation marker, αSMA is expressed by VSMCs of endometrial vessels, by pericytes attached to capillaries, and by stromal myofibroblasts (21,22). Increased αSMA expression during the secretory phase (22) suggests a correlation between endometrial vascular maturation with αSMA expression. ...
... As an early differentiation marker, αSMA is expressed by VSMCs of endometrial vessels, by pericytes attached to capillaries, and by stromal myofibroblasts (21,22). Increased αSMA expression during the secretory phase (22) suggests a correlation between endometrial vascular maturation with αSMA expression. In support of this thesis, the VSMC proliferation index (24) and the number of endometrial vessels enveloped by more than one VSMC layer increases from the proliferative to secretory phase (25). ...
Significance
Over a million unintended pregnancies occur in the United States each year because of either discontinuation or misuse of contraceptives. The major reason for discontinuation of long-acting progestin-only contraceptives (LAPCs) is the occurrence of abnormal uterine bleeding (AUB). Uncovering the mechanisms underlying LAPC-induced AUB is essential to prevent their discontinuation. We found that LAPCs reduce proliferation of human and guinea pig endometrial vascular smooth muscle cells (VSMCs), resulting in production of thin-walled hyperdilated fragile microvessels. In cultured VSMCs, chemokine (C-C motif) ligand 2 reverses LAPC-mediated inhibition of VSMC proliferation, suggesting that LAPCs impair endometrial vascular integrity and that chemokine ligand 2 administration may prevent LAPC-induced AUB.
... Specimens obtained at 1 h, 3 h and 6 h following spasm provocation and two and four weeks following spasm provocation were used for staining. The following cell markers were examined: β-actin (monoclonal anti-β-actin clone AC-15, mouse ascites fluid, Sigma Corporation, USA), a cytoskeletal actin and marker of the synthetic phenotype of VSMCs in vitro (10); CD34 (rabbit monoclonal anti-human CD34 antibody, clone EP 373Y, Epitomics Inc, USA), a marker of bone marrow mesenchymal cells (11); α-smooth muscle actin (α-SMA; mouse anti-human SMA, clone/klon 1A4, code number M0851, Dako Epos, Denmark) and vimentin (rabbit anti-human vimentin antibody, clone Vim 3B4, code number U7034, Dako Epos, Denmark), markers of matured VSMCs, fibroblasts and myofibroblasts (12,13); smooth muscle myosin heavy chain-1 (SM-1) (mouse monoclonal anti-human SM-1 antibody, clone 3F8, Abcam Inc, USA), a specific marker of mature VSMCs (14); N-cadherin (rabbit monoclonal anti-human N-cadherin antibody, clone ESR 1792Y, Epitomics Inc, USA), a specific marker of myofibroblasts (15); and CD31 (rabbit monoclonal anti-human CD31 antibody/PECAM-1, clone EP 3093, Abgent Inc, USA), a marker of endothelial cells (11). ...
Coronary intimal hyperplasia occurs at the site of spasm in patients with vasospastic angina. The migration of vascular smooth muscle cells (VSMCs) from the media has been proposed as a potential mechanism; however, this has not been confirmed with supportive evidence.
To determine which cell types participate in spasm-induced coronary intimal hyperplasia.
Morphological changes in spastic coronary artery segments in beagles were examined using electron microscopy and immunohistochemical staining of cell markers at 1 h, 3 h and 6 h, and two and four weeks after spasm provocation.
Small smooth muscle-like cells (SMLCs) were observed in the media of nonspastic coronary segments using electron microscopy. These cells attached side-to-side to large, known VSMCs. At 1 h to 6 h after spasm provocation, SMLCs separated from VSMCs, changed to an amoebic configuration and migrated through cleaved junctions or disrupted portions of the internal elastic lamina into the subendothelial space. The SMLCs expressed alpha-smooth muscle actin and N-cadherin, but not smooth muscle myosin heavy chain-1 and β-actin, suggesting that they were myofibroblasts and not a synthetic phenotype of VSMCs. Intimal hyperplasia was observed in all preparations at two and four weeks after spasm provocation. Furthermore, alpha-smooth muscle actin-positive SMLCs, often amoebic in configuration, were observed in the hyperplastic intima.
On coronary spasm provocation, SMLCs (ie, possible myofibroblasts) resident in the media migrate as a spearhead into the intima and play a role in coronary intimal hyperplasia.
... Endometrial receptivity can be an important determinant of fertility in woman with unexplained causes. Preparation of a receptive endometrium requires changes in its pattern, thickness and angiogenesis which are accompanied by the increase in vascular permeability that not only supports endometrial proliferation but at the same time transforms thin dense endometrium into thick, highly permeable secretory endometrium [2]. Implantation of the fertilized ovum in endometrium is a dynamic process [3,4]. ...
... In order to survive and grow, endometrial cells and stroma must acquire a blood supply; indeed, during a menstrual cycle there are waves of active angiogenesis within the endometrium, with the development of arterioles and a capillary network, an event involving a spatially regulated process of vascular smooth cell differentiation, which is under the influence of a number of factors [16]. The activity of some of these factors in women with adenomyosis has now been investigated with interesting results. ...
Eutopic and ectopic endometria of women with adenomyosis show a series of metabolic and molecular abnormalities that increase angiogenesis and proliferation, decrease apoptosis, allow local production of estrogens, create progesterone resistance, and impair cytokine expression. These changes enhance the ability of the endometrium to infiltrate the junctional zone myometrium and the growth of ectopic tissue. In addition, in these subjects several immunological abnormalities have been observed, together with an increased production of 'free radicals' leading to excessive growth of endometrial stromal cells that may facilitate the establishment of adenomyosis. A limiting factor is that these studies have been performed on hysterectomy specimens representing final stages of the disease. This increased knowledge has created new therapeutic options, including the block of local aromatase production through the use of selective estrogen receptor modulators, estrogen-progestin combinations and gonadotropin-releasing hormone super agonists. Also promising are investigations into the mechanism of dysmenorrhea and abnormal uterine bleeding.
... Menstrual cycles produce waves of active angiogenesis within the endometrium, with development of arterioles and a capillary network. Kohnen et al. found that this involves a spatially regulated process of vascular smooth cell differentiation, which is under the influence of a number of factors [33]. Very recently, Goteri et al. demonstrated that, in women with adenomyosis, VEGF (a major mediator of angio genesis and vascular permeability), hypoxia-inducible factor (HIF)-1a expression and microvessel density were increased, particularly in epithelial cells, when comparing heterotopic versus normotopic endometrium in the same woman [34]. ...
In the early days, all mucosal invasions of abdominal organs were considered to be one pathological condition of uncertain origin, termed adenomyoma. It was only in the 1920s that endometriosis and adenomyosis were clearly separated and it took approximately 80 years to put forward a new theory reunifying their pathogenesis. Today, identification of adenomyosis is carried out exclusively through vaginal ultrasonography and MRI. These techniques have made a careful evaluation of a distinct anatomical structure and the inner myometrial layers underlying the endometrium, termed the junctional zone, possible. Adenomyosis is characterized by a homogeneous thickening of this portion of the myometrium. When this hyperplasia is associated to an alteration of spiral arterioles' angiogenesis, then both adenomyosis and endometriosis may develop. Evidence is being accumulated that pre-eclampsia, fetal growth restriction and premature delivery may be linked, together representing a new, major obstetrical syndrome characterized by a modified uterine environment around the time of nidation. A dozen different medical or surgical techniques are utilized for the treatment of adenomyosis and novel approaches are being tested. These include use of inhibitors of angiogenesis that have been shown to cause reduced neo-angiogenesis, a significant modification of gene expression and a decrease in the percentage of active lesions. Encouraging results have also been obtained with the levonorgestrel-releasing intrauterine system.
... [3][4][5][6], 79 a marker of late differentiation in vascular smooth muscle cells. 56 Placental vasculogenesis was significantly reduced as indicated by lack of CD34 expression by individual foetal blood vessels, 79 similar to the abnormal placental vasculogenesis observed with spontaneous abortions in humans. 101 In both ovine and bovine SCNT pregnancies, some investigators report that reduction in villous vascularization is accompanied by hypoplasia of trophoblastic epithelial cells, apoptosis and shedding of trophoblastic epithelial cells from foetal villi, 28 and/or reduced numbers of the trophoblastderived binucleate cells. ...
Cloning of cattle, sheep, and mice by somatic cell nuclear transfer (SCNT) can result in apparently healthy offspring, but the probability of a successful and complete pregnancy is less than 5%. Failures of SCNT pregnancy are associated with placental abnormalities, such as placentomegaly, reduced vascularisation, hypoplasia of trophoblastic epithelium, and altered basement membrane. The pathogenesis of these changes is poorly understood, but current evidence implicates aberrant reprogramming of donor nuclei by the recipient oocyte cytoplast, resulting in epigenetic modifications of key regulatory genes essential for normal placental development. The purpose of this review is to provide an overview of the anatomic pathology of abnormal placentae of SCNT clones and to summarize current knowledge concerning underlying pathogenetic mechanisms.
... During this process of arteriogenesis, the capillaries acquire a vascular smooth muscle coat, thereby gaining the ability to regulate blood flow. VSMCs differentiate from mesenchymal cells in a spatially regulated fashion, expressing a series of characteristic markers with a progressive increase in cytoskeletal complexity (Kohnen et al., 2000; Rogers and Abberton, 2003). Two cytoskeletal markers were investigated: aSMA, an early marker of smooth muscle differentiation, and SMM, which is expressed later (Kohnen et al., 2000; Rogers and Abberton, 2003). ...
... VSMCs differentiate from mesenchymal cells in a spatially regulated fashion, expressing a series of characteristic markers with a progressive increase in cytoskeletal complexity (Kohnen et al., 2000; Rogers and Abberton, 2003). Two cytoskeletal markers were investigated: aSMA, an early marker of smooth muscle differentiation, and SMM, which is expressed later (Kohnen et al., 2000; Rogers and Abberton, 2003). The quantification of VSMC development and differentiation was first reported by Rogers and Abberton (2003) in the context of pathological endometrial bleeding; endometrial arterioles were described as initially partially coated with VSMC before being completely surrounded . ...
Increased numbers of phenotypically unusual CD56(bright) CD16- uterine natural killer (uNK) cells have been associated with recurrent reproductive failure. uNK cells produce angiogenic growth factors and are potential regulators of decidual angiogenesis in early pregnancy. The final common mechanism for early pregnancy loss is thought to be early onset of the maternal circulation and excessive placental oxidative stress. We tested the hypothesis that increased uNK cells in preimplantation endometrium are associated with altered angiogenesis.
Women with recurrent reproductive failure (n = 122) were investigated with uterine artery Doppler and endometrial biopsy. Immunohistochemistry was used to identify uNK, endothelial and vascular smooth muscle cells and image analysis was used to assess location, density and differentiation.
uNK cell density was positively correlated with the formation of blood (P = 0.005, r = 0.5) and lymphatic vessels (P = 0.0001, r = 0.6), spiral arteriole smooth muscle differentiation (P = 0.01, r = 0.5) and endometrial oedema (P = 0.004). The functional effect of this was a reduced uterine artery resistance to blood flow.
These data suggest that uNK cells may regulate angiogenesis in non-pregnant endometrium. The mechanisms of reproductive failure associated with increased uNK cell density appear to be increased angiogenesis and peri-implantation blood flow, which may lead to early maternal circulation and hence pregnancy failure due to excessive oxidative stress.
