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CCM2 and CCM3 Proteins Contribute to Vasculogenesis and Angiogenesis in Human Placenta

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CCM2 and CCM3 Proteins Contribute to Vasculogenesis and Angiogenesis in Human Placenta Histol Histopathol (2009) 24: 1287-1294 Histology and http://www.hh.um.es Histopathology Cellular and Molecular Biology CCM2 and CCM3 proteins contribute to vasculogenesis and angiogenesis in human placenta Gamze Tanriover1, Yasemin Seval1, Leyla Sati1, Murat Gunel2 and Necdet Demir1 1Department of Histology and Embryology, Akdeniz University, School of Medicine, Antalya, Turkey and 2 Department of Neurosurgery, Yale University, School of Medicine, New Haven, CT, USA Summary. Placenta as an ideal model to study Introduction angiogenic mechanisms have been established in previous studies. There are two processes, The placenta is a multifaceted organ that plays a vasculogenesis and angiogenesis, involved in blood critical role in maintaining and protecting the developing vessel formation during placental development. fetus. Normal development and function of the placenta Therefore, blood vessel formation is a crucial issue that requires extensive vasculogenesis and subsequent might cause vascular malformations. One of the vascular angiogenesis, in both maternal and fetal tissues. malformations is cerebral cavernous malformation Vasculogenesis is the formation of the primitive vascular (CCM) in the central nervous system, consisting of network de novo from progenitor cells, and angiogenesis endothelium-lined vascular channels without intervening is identified as the extension of blood vessels from normal brain parenchyma. Three CCM loci have been preexisting vascular structures (Demir et al., 1989, 2006; mapped as Ccm1, Ccm2, Ccm3 genes in CCM. In order Geva et al., 2002; Charnock-Jones et al., 2004). Many to investigate whether CCM proteins participate in blood factors, such as vascular endothelial growth factor vessel formation, we report here the expression patterns (VEGF), angiopoietins (Angpt-1 and -2) and their of CCM2 and CCM3 in developing and term human receptors are involved in the molecular regulation of placenta by means of immunohistochemistry and these diverse developmental steps. The spatial and Western blot analysis. CCM2 and CCM3 were obviously temporal localization of these factors have been studied detected in the vascular endothelium during early extensively in the placenta (Geva et al., 2002; Demir et pregnancy. Moreover, vascular endothelium of stem villi al., 2006). revealed a moderate immunostaining for CCM2 and, to a It is well known that genetic and angiogenic factors lesser extent, in the endothelium of mature intermediate also play an important role in the pathogenesis of several villi in term placenta. Interestingly, CCM3 immuno- vascular anomalies in human placenta (Breier, 2000; staining was weakly localized in the endothelium of Reynolds and Redmer, 2001; Reynolds et al., 2002). mature intermediate villi and showed lesser expression Considerable advances have been made in recent years going toward stem villi in term placenta. The expression to identify the genetic and molecular determinants of a patterns of the proteins were clearly identified in the variety of vascular anomalies using molecular genetic vascular endothelium of human placenta, suggesting that approaches. So far, several genes have been defined in they might play roles during angiogenesis and vascular anomalies, such as cerebral cavernous vasculogenesis. Furthermore, with this study, CCM2 and malformations (CCMs). CCMs are vascular CCM3 have been described for the first time in the malformations that can occur as a sporadic or a familial human placenta. autosomal dominant disorder with incomplete penetrance and variable clinical expressions (Liquori et Key words: CCM2, CCM3, Placenta, Angiogenesis, al., 2007). CCMs are also characterized by abnormally Vasculogenesis enlarged capillary cavities without intervening brain parenchyma (Clatterbuck et al., 2001) that can result in Offprint requests to: Necdet DEMIR, Assoc. Prof., Department of seizures, hemorrhage, recurrent headaches, and focal Histology and Embryology, Faculty of Medicine, Akdeniz University, neurological deficits (Felbor et al., 2006). Up to now, 07070 Antalya, Turkey. e-mail: [email protected] three CCM loci have been identified; on chromosomes 1288 CCM2, CCM3 proteins and vascularization of the human placenta 7q21-22 (Ccm1; Online Mendelian Inheritance in Man Akdeniz University, Antalya, Turkey. Informed consent [OMIM] 116860), 7p13-15 (Ccm2; OMIM 603284), and forms and protocols to use the tissues were approved by 3q25.2-27 (Ccm3; OMIM 603285), and 3 genes have the Ethical Committee of School of Medicine, Akdeniz been cloned, KRIT1 on Ccm1, MGC4607 on Ccm2, and University, Antalya, Turkey. PDCD10 on Ccm3 (Revencu and Vikkula, 2006). Immediately after obtaining the tissues, placental The mechanisms involved in cerebral blood vessel samples were divided into two parts, one of which was angiogenesis during development are still poorly embedded in paraffin for further immunohistochemical defined. Therefore, there is a lack in the understanding analysis, while the other one was preserved in liquid of the mechanisms that lead to CCMs. The identification nitrogen for Western blot analysis. of the CCM genes has broadened the understanding of the mechanisms underlying CCMs. Recent studies have CCM2 and CCM3 antibody production indicated possible angiogenic functions of these genes (Plummer et al., 2005; Revencu and Vikkula, 2006). A CCM3/PDCD10 (CCM3)-specific rabbit Guzeloglu-Kayisli et al. (2004) reported that CCM1 was polyclonal antibody was synthesized and affinity- expressed in endothelial cells of human placenta using a purified against the antigenic peptide KIPDEINDRVR well-established in vivo model of angiogenesis by FLQTIKD (Open Biosystems, Huntsville, AL) as detailed histological examination. They pointed out that previously described (Tanriover et al., 2008). The CCM2 CCM1 was expressed during early angiogenesis by antibody synthesis, characterization and validation have endothelial cells and may play a key role in vessel been previously described (Seker et al., 2006). formation and/or development. However, there is still no knowledge about whether CCM2 and CCM3 would also Immunohistochemistry have a role, like CCM1, in human placenta, as observed in the central nervous system. For CCM2 and CCM3 immunohistochemistry, We hypothesized that as indicated for CCM1 by paraffin sections were deparaffinized and blocked for Guzeloglu-Kayisli et al. CCM2 and CCM3 might also be endogenous peroxidase activity with methanol involved in angiogenesis in both early and term human containing 3% H2O2 for 15 min and for nonspecific placenta (Guzeloglu-Kayisli et al., 2004). Therefore, our binding with universal blocking reagent (BioGenex, San aim was to investigate the expression and distribution of Ramon, CA, USA) for 10 min at room temperature CCM2 and CCM3 proteins in human placental tissues (Tanriover et al., 2005). Anti-rabbit CCM2 and CCM3 during development, and to determine whether there diluted in dilution buffer (1/250) were applied for 1h at were any alterations in their expression by using room temperature in a humidified chamber. For negative immunohistochemistry and Western blot analysis. This is controls the primary antibodies were replaced by normal so far the first study which has attempted to determine rabbit IgG serum (Vector Lab. Burlingame, CA, USA) at CCM2 and CCM3 expression in human placental the same concentration. After several washes in PBS, tissues. sections were incubated with biotinylated goat anti- rabbit IgG secondary antibody (1/400 dilution Vector Materials and methods Lab. Burlingame, CA, USA) for 30 min followed by LSAB streptavidin-peroxidase complex (Dako, Tissue collection Carpinteria, CA, USA) incubation for 30 min and were rinsed with PBS. Antibody complexes were visualized A total of 14 samples of human placental tissues [5 by incubation with diaminobenzidine (DAB) chromogen samples of 22-28 days (fourth week pc.); 5 samples of (BioGenex). Sections were counterstained with Mayer's 29-35 days (fifth week pc.); 4 samples of 36-42 days hematoxylin (Dako), dehydrated, mounted and examined (sixth week pc.)] in the first trimester obtained after legal by a Zeiss-Axioplan (Oberkochen, Germany) termination of pregnancy by curettage for medical or microscope. psychosocial reasons, which were unlikely to affect placental structure and function. Furthermore, a total of Analysis of staining intensities 6 term human placentas collected from clinically normal pregnancies terminated by vaginal deliveries were also The intensity of immunoreactivity was quantitatively studied. Tissues were classified as described previously evaluated by two observers blinded to the type and (Demir et al., 1989) by assessing the embryonic source of the tissues, in which positive stainings were developmental stages according to the Carnegie grouped according to the following categories: 0 (no classification (O'rahilly, 1973). None of the normal staining), + (weak but detectable), ++ (moderate or pregnancies were receiving hormone treatment. The distinct), +++ (strong) and ++++ (very intense) (Sati et umbilical vessels of term placenta were dissected and al., 2007). The results are presented in Table 1. clamped for the perfusion of each placental vascular bed with a phosphate buffered saline solution. Double immunohistochemistry Tissues were supplied from the Department of Obstetrics and Gynecology, School of Medicine, Until the primary antibody step, the same protocol 1289 CCM2, CCM3 proteins and vascularization of the human placenta was applied to the slides for
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