The role of KDR in intrauterine adhesions may involve the TGF-β1/Smads signaling pathway

Abstract

The aim of this study was to investigate the role of kinase-insert domain-containing receptor (KDR) in intrauterine adhesions (IUA) and its mechanism. The Case group consisted of 92 patients diagnosed with IUA, and the Control group included 86 patients with uterine septum who had normal endometrium verified with an uteroscope. In addition, 50 rats were randomly assigned into Control, Sham, Model, NC-siRNA, and KDR-siRNA groups. Rats in the Model, NC-siRNA, and KDR-siRNA groups were induced by uterine curettage and lipopolysaccharide (LPS) treatment to establish the IUA model. Then, immunohistochemistry was applied for detection of VEGF and KDR expression, HE staining was used for observation of the endometrial morphology and gland counting, Masson staining for measurement of the degree of endometrial fibrosis, and qRT-PCR and western blot for the expression of KDR, VEGF, MMP-9, as well as TGF-β1/Smads pathway-related proteins. Compared with the Control group, the mRNA and protein expressions of KDR were significantly higher in IUA endometrial tissues, and the expression of KDR was positively correlated to the severity of IUA. In addition, the injection of si-KDR increased the number of endometrial glands, reduced the area of fibrosis, inhibited mRNA and protein expression of KDR and VEGF, up-regulated the expression of MMP-9 and Smad7, and decreased the expression level of TGF-β1, p-Smad2, p-Smad3, and Smad4 in rats with IUA. Highly-expressed KDR was related to patients' severity of IUA, and silencing KDR may prevent the occurrence and development of IUA via TGF-β1/Smads signaling pathway and up-regulating the expression of MMP-9.

Human Acellular Amniotic Matrix with Previously Seeded Umbilical Cord Mesenchymal Stem Cells Restores Endometrial Function in a Rat Model of Injury

“…In consistence with the previous studies [ 58 , 59 ], our results demonstrated that the mRNA expression of VEGF in endometrium in the UCMSC-AAM group decreased compared with the injury group and AAM group, higher than that of the normal group, indicating the mitigation of fibrosis after transplantation of UCMSC-AAM. It is reported that the expression of VEGF can be regulated by various growth factors and cytokines (EGF, TGF β , PGE2, IL-1, IL-6) [ 60 ].…”

Focus on the Primary Prevention of Intrauterine Adhesions: Current Concept and Vision

“…Many strategies or principles for decreasing the risk of developing IUA, such as the reduced use of electrosurgery and the minimization of trauma to the healthy endometrium and myometrium, have been proposed [ 73 , 74 , 75 , 76 , 77 , 78 , 79 ]. Additionally, many biomaterial agents, barrier methods, and cell or bio-agent therapies have been applied [ 14 , 16 , 24 , 27 , 28 , 29 , 30 , 31 , 35 , 37 , 40 , 43 , 44 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ]. Figure 3 shows the recent development of agents available for the primary prevention of IUA after uterine surgery.…”

“…One involves the avoidance of over- or purulent inflammatory processes or over-traumatic injury; the second is a barrier method to prevent the attachment of the bilateral traumatic surface; the third is the enhancement of regeneration ability; the last is early intervention via repeat hysteroscopy to remove the thin or immature adhesion band ( Figure 3 ). The tools include agents (drugs) or physical (mechanical) barriers to cover the uterine lining side, or separate the opposing sides of the uterine linings immediately after hysteroscopic surgery; the prescription of estrogen use postoperatively, postoperative gonadotropin-releasing hormone agonist injection, or immediate postoperative antibiotics use; and the use of biomaterials or new technologies such as cellular therapy [ 5 , 6 , 7 , 8 , 9 , 10 , 14 , 23 , 24 , 27 , 28 , 29 , 30 , 31 , 32 , 35 , 36 , 37 , 39 , 40 , 41 , 42 , 43 , 56 , 57 , 58 , 59 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 86 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , …”

“…In the absence of conception and implantation, endometrial stroma cells sense hormone withdrawal, and upregulate intracellular signaling and the release of inflammatory and growth factors, contributing to vasoconstriction of the uterine vessels, recruitment of inflammatory and immune cells as well as relatively immune-privileged endometrial mesenchymal stem cells, and propagation of the menstrual cascade to aid in the regeneration and repairing process after menstruation, in concert with processes such as epithelial–mesenchymal transition/mesenchymal–epithelial transition (EMT/MET) and Wnt signaling, to restore endometrial homeostasis [ 14 ]. Furthermore, the activation of endometrial epithelial progenitor cells (N-cadherin+, E-cadherin+, and vimentin+ cells) and perivascular mesenchymal stem cells located in the basal layer near the endometrial–myometrial border, as well as within the functional layer, possibly involving Wnt or Notch signaling system, drives cellular replacement in the glands and stroma layer, respectively, to finish endometrial regeneration and maintain the endometrial integrity [ 3 ].…”

Recent Advances in Understandings Towards Pathogenesis and Treatment for Intrauterine Adhesion and Disruptive Insights from Single-Cell Analysis

“…Wang et al [ 33 ] also reported that NF-κB was highly expressed in endometrial tissues of IUA patients and therefore a putative pathogenic factor for IUA. Chen et al [ 30 ] found that the expression of KDR in IUA tissues was significantly higher than that of the normal counterpart, and also the expression of KDR was positively correlated with the severity of IUA. Silencing KDR could upregulate MMP-9 and affect TGF-β1/SMAD pathway to inhibit the occurrence and development of IUA, so KDR was thought to play an important role in the formation of IUA.…”