Disturbed Angiogenesis Research Articles

Circulating Neurovascular Guidance Molecules and Their Relationship with Peripheral Microvascular Impairment in Systemic Sclerosis.

Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease whose earliest clinical manifestations are microvascular tone dysregulation and peripheral microcirculatory abnormalities. Following previous evidence of an association between circulating neurovascular guidance molecules and SSc disturbed angiogenesis, here, we measured the levels of soluble neuropilin 1 (sNRP1), semaphorin 3E (Sema3E), and Slit2 by enzyme-linked immunosorbent assay in serum samples from a large case series of 166 SSc patients vs. 110 healthy controls. We focused on their possible correlation with vascular disease clinical features and applied logistic regression analysis to determine which of them could better reflect disease activity and severity. Our results demonstrate that, in SSc: (i) sNRP1 is significantly decreased, with lower sNRP1 serum levels correlating with the severity of nailfold videocapillaroscopy (NVC) abnormalities and the presence of ischemic digital ulcers (DUs); (ii) both Sema3E and Slit2 are increased, with Sema3E better reflecting early NVC abnormalities; and (iii) higher Sema3E correlates with the absence of DUs, while augmented Slit2 associates with the presence of DUs. Receiver operator characteristics curve analysis revealed that both circulating sNRP1 and Sema3E show a moderate diagnostic accuracy. Moreover, logistic regression analysis allowed to identify sNRP1 and Sema3E as more suitable independent biomarkers reflecting the activity and severity of SSc-related peripheral microvasculopathy.

Liraglutide via Activation of AMP-Activated Protein Kinase-Hypoxia Inducible Factor-1α-Heme Oxygenase-1 Signaling Promotes Wound Healing by Preventing Endothelial Dysfunction in Diabetic Mice.

Background/Aims: Diabetic foot ulcers (DFUs) present a major challenge in clinical practice, and hyperglycemia-induced angiogenesis disturbance and endothelial dysfunction likely exacerbate DFUs. The long-acting glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira) is a potential activator of AMP-activated protein kinase (AMPK) that appears to enhance endothelial function and have substantial pro-angiogenesis and antioxidant stress effects. Therefore, in this study, we aimed to investigate whether the protective role of Lira in diabetic wound healing acts against the mechanisms underlying hyperglycemia-induced endothelial dysfunction and angiogenesis disturbance.Methods: Accordingly, db/db mice were assessed after receiving subcutaneous Lira injections. We also cultured human umbilical vein endothelial cells (HUVECs) in either normal or high glucose (5.5 or 33 mM glucose, respectively) medium with or without Lira for 72 h.Results: An obvious inhibition of hyperglycemia-triggered endothelial dysfunction and angiogenesis disturbance was observed; follow by a promotion of diabetic wound healing under Lira treatment combined with restored hyperglycemia-impaired AMPK signaling pathway activity. AMPKα1/2 siRNA and Compound C (Cpd C), an inhibitor of AMPK, abolished both Lira-mediated endothelial protection and pro-angiogenesis action, as well as the diabetic wound healing promoted by Lira. Furthermore, hypoxia inducible factor-1α (Hif-1α; transcription factors of AMPK substrates) knockdown in HUVECs and db/db mice demonstrated that Lira activated AMPK to prevent hyperglycemia-triggered endothelial dysfunction and angiogenesis disturbance, with a subsequent promotion of diabetic wound healing that was Hif-1α–heme oxygenase-1 (HO-1) axis-dependent. Taken together, these findings reveal that the promotion of diabetic wound healing by Lira occurs via its AMPK-dependent endothelial protection and pro-angiogenic effects, which are regulated by the Hif-1α–HO-1 axis.

Ефективність превентивних методів їх комбінацій у профілактиці передчасних пологів

Prediction and prevention of premature birth is a significant problem of modern obstetrics. The use of ultrasound cervicometry and the index of placental angiogenesis for the prediction of premature birth is promising. The aim of the study was to investigate the effectiveness of cerclage, pessary, intravaginal progesterone or their combinations in the prevention of premature birth. A total of 292 pregnant women were examined. They were divided into several groups according to the results of the detection of cervical length and the level of the ratio between placental growth factor (PlGF) and fms-like tyrosine kinase (sFlt-1). Group I included women with a negative screening’ resuls. Other groups included women with a «short» cervix and disturbed placental angiogenesis. In group II, women with cervical cerlage were observed. In group III — used a pessary; Group IV — vaginal progesterone; V — cobined use of cerclage and pessary; and in VI — use of cerclage and vaginal progesterone. The pregnancy was completed at term in 159 patients, and 133 women had preterm delivery. Among patients who had positive miscarriage screening results, the use of preventive measures or combinations resulted in fairly equal results. However, the use of progesterone and cervical cerclage has shown the best efficacy. Some limitations in this study were the small sample size and the lack of information on the use of anticoagulants, disaggregants and tocolytics in the examined women.

Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension

Environmental and epigenetic factors often play an important role in polygenic disorders. However, how such factors affect disease-specific tissues at the molecular level remains to be understood. Here, we address this in pulmonary arterial hypertension (PAH). We obtain pulmonary arterial endothelial cells (PAECs) from lungs of patients and controls (n = 19), and perform chromatin, transcriptomic and interaction profiling. Overall, we observe extensive remodeling at active enhancers in PAH PAECs and identify hundreds of differentially active TFs, yet find very little transcriptomic changes in steady-state. We devise a disease-specific enhancer-gene regulatory network and predict that primed enhancers in PAH PAECs are activated by the differentially active TFs, resulting in an aberrant response to endothelial signals, which could lead to disturbed angiogenesis and endothelial-to-mesenchymal-transition. We validate these predictions for a selection of target genes in PAECs stimulated with TGF-β, VEGF or serotonin. Our study highlights the role of chromatin state and enhancers in disease-relevant cell types of PAH.

The glucose degradation product methylglyoxal induces immature angiogenesis in patients undergoing peritoneal dialysis

The accumulation of glucose degradation products (GDPs) can lead to tissue damage in patients with diabetes and those undergoing long-term peritoneal dialysis (PD). Angiogenesis is occasionally observed in the peritoneal membrane of patients undergoing PD, where it is associated with failure of ultrafiltration. To investigate the mechanism underlying the influence of angiogenesis on fluid absorption, we evaluated the effects of accumulation of the glucose degradation product methylglyoxal (MGO) on angiogenesis in vitro, and analyzed the association with angiogenesis in the peritoneal membrane. To this end, we measured the levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF)-BB in cultured endothelial and smooth muscle cells after administration of MGO. The expression of PDGF-BB mRNA and protein decreased significantly after exposure to MGO, while the expression of VEGF mRNA increased (both P < 0.01). The expression of PDGF-Rβ mRNA in cultured smooth muscle cells did not change after administration of MGO, although the expression of VEGF mRNA increased (P < 0.01). We also evaluated the associations between the number of capillary vessels, peritoneal function, and the degree of MGO deposition using peritoneum samples collected from patients undergoing PD. The number of immature capillary vessels was significantly associated with peritoneal dysfunction and the degree of MGO accumulation (both P < 0.01). In conclusion, MGO enhances the production of VEGF and suppresses the production of PDGF-BB, potentially leading to disturbance of angiogenesis in the peritoneal membrane. Accumulation of MGO in the peritoneum may cause immature angiogenesis and peritoneal dysfunction.

Hearing impairment and associated morphological changes in pituitary adenylate cyclase activating polypeptide (PACAP)-deficient mice

Pituitary adenylate cyclase activating polypeptide (PACAP) is a regulatory and cytoprotective neuropeptide, its deficiency implies accelerated aging in mice. It is present in the auditory system having antiapoptotic effects. Expression of Ca2+-binding proteins and its PAC1 receptor differs in the inner ear of PACAP-deficient (KO) and wild-type (WT) mice. Our aim was to elucidate the functional role of PACAP in the auditory system. Auditory brainstem response (ABR) tests found higher hearing thresholds in KO mice at click and low frequency burst stimuli. Hearing impairment at higher frequencies showed as reduced ABR wave amplitudes and latencies in KO animals. Increase in neuronal activity, demonstrated by c-Fos immunolabeling, was lower in KO mice after noise exposure in the ventral and dorsal cochlear nuclei. Noise induced neuronal activation was similar in further relay nuclei of the auditory pathway of WT and KO mice. Based on the similar inflammatory and angiogenic protein profile data from cochlear duct lysates, neither inflammation nor disturbed angiogenesis, as potential pathological components in sensorineural hearing losses, seem to be involved in the pathomechanism of the presented functional and morphological changes in PACAP KO mice. The hearing impairment is probably concomitant with the markedly accelerated aging processes in these animals.

Biochemical markers and effectivity of the preventive therapy of the fetal distress and preterm delivery in pregnant women with polyhydramnios

Polyhydramnios in pregnant women are one of the most frequent pathologies in obstetrics, which is caused by an increase in the use of ultrasound screening of pregnant women and ranges from 1–3 to 8%. The aim of the study was to evaluate changes in blood biochemical parameters, biophysical profile of the fetus and the health status of newborns in pregnant women with polyhydramnios during the prophylactic therapy of this pathology and to estimate the frequency of polyhydramnios occurrence under the influence of preventive therapy in pregnant women at risk of polyhydramnios. We examined 120 pregnant women at gestational age from 20 to 38 weeks between the ages of 20 and 39 years: 1 group consisted of 30 healthy pregnant women, 2 group — 90 pregnant women with chronic polyhydramnios, which was divided into two subgroups: 40 pregnant women without fetal distress in 1 subgroup and 50 pregnant women with fetal distress in 2 subgroups. 1 subgroup of pregnant women received prophylactic Magnerot, Tivortin, Larnamine, Lymphomyosot and vitamin D3. The 2nd subgroup of pregnant women received traditional treatment according to the clinical protocol of the Ministry of Health of Ukraine №900 dated December 27, 2006, №782 dated December 29, 2005. Prenatal diagnosis was carried out by the method of enzyme-linked immunosorbent assay: the metabolite level of vitamin D-25 OH(D) was determined, anti-inflammatory cytokines IL–10, IL–6, vascular endothelial growth factor VEGF, malonic aldehyde, carbonyl groups of proteins, superoxide dismutase, serum protein content. Conducted ultrasound examination of the fetus and dopplerometry of uterine-placental vessels, cardiotocography of the fetus, evaluated the biophysical profile of the fetus. The significance of the difference between the compared groups was determined using Student's t test. In pregnant women with chronic polyhydramnios, a decrease in endogenous glutathione antioxidant reserves, a decrease in the activity of the superoxide dismutase antioxidant enzyme, an increase in the activity of the pro-oxidant enzyme xanthine oxidase and the presence of cytokine imbalance have been found. It is shown that among all biochemical changes in the body of pregnant women with chronic polyhydramnios, vitamin D deficiency, inflammation and disturbance of angiogenesis play the most important role in the development of fetal distress. Pregnant women at high risk of polyhydramnios who received the proposed preventive therapy for fetal distress, improved fetoplacental blood flow, decreased the percentage of placental dysfunction by 1.8 times, fetal distress — by 1.5 times, premature birth — by 2 times, decreased asphyxia in newborns 1.7 times, the rate of perinatal morbidity in newborns decreased 1.9 times, compared with the group of pregnant women receiving traditional therapy. Thus, the positive effect of preventive therapy of pathology of pregnant women with polyhydramnios was confirmed clinically and biochemically.

Resveratrol Promotes Diabetic Wound Healing via SIRT1-FOXO1-c-Myc Signaling Pathway-Mediated Angiogenesis.

Background/Aims: Diabetic non-healing skin ulcers represent a serious challenge in clinical practice, in which the hyperglycemia-induced disturbance of angiogenesis, and endothelial dysfunction play a crucial role. Resveratrol (RES), a silent information regulator 1 (SIRT1) agonist, can improve endothelial function and has strong pro-angiogenic properties, and has thus become a research focus for the treatment of diabetic non-healing skin ulcers; however, the underlying mechanism by which RES regulates these processes remains unclear. Therefore, the present study was intended to determine if RES exerts its observed protective role in diabetic wound healing by alleviating hyperglycemia-induced endothelial dysfunction and the disturbance of angiogenesis.Methods: We investigated the effects of RES on cell migration, cell proliferation, apoptosis, tube formation, and the underlying molecular mechanisms in 33 mM high glucose-stimulated human umbilical vein endothelial cells (HUVECs) by semi-quantitative RT-PCR, western blot analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and immunofluorescence in vitro. We further explored the role of RES on endothelial dysfunction and wound healing disturbance in db/db mice by TUNEL staining, immunofluorescence, and photography in vivo.Results: We observed an obvious inhibition of hyperglycemia-triggered endothelial dysfunction and a disturbance of angiogenesis, followed by the promotion of diabetic wound healing via RES, along with restoration of the activity of the hyperglycemia-impaired SIRT1 signaling pathway. Pretreatment with EX-527, a SIRT1 inhibitor, abolished the RES-mediated endothelial protection and pro-angiogenesis action, and then delayed diabetic wound healing. Furthermore, examination of the overexpression of forkhead box O1 (FOXO1), a transcription factor substrate of SIRT1, in HUVECs and db/db mice revealed that RES activated SIRT1 to restore hyperglycemia-triggered endothelial dysfunction and disturbance of angiogenesis, followed by the promotion of diabetic wound healing in a c-Myc-dependent manner. Pretreatment with 10058-F4, a c-Myc inhibitor, repressed RES-mediated endothelial protection, angiogenesis, and diabetic wound healing.Conclusion: Our findings indicate that the positive role of RES in diabetic wound healing via its SIRT1-dependent endothelial protection and pro-angiogenic effects involves the inhibition of FOXO1 and the de-repression of c-Myc expression.

Disturbed angiogenesis in intrauterine growth restriction-compromised placentas at term

Purpose of investigation: The aim of this study was to compare levels of selected angiogenesis-related proteins in intrauterine growth restriction (IUGR)-compromised and normal placentas at term. Materials and Methods: Stromatal tissue of placental villi of gestationally matched IUGR patients and controls (both groups of n=32, gestational age between 39+0 and 40+6 gtt) was separated by microdissection. After separation, placental tissue was homogenised on ice (2′10 min, 2,000 rpm) and centrifuged (2'5 min, 5,000 rpm). Proteins of supernatant were fractionated by 8% or 10% SDS-PAGE and Tie-1, Tie-2, VEGFR-1, VEGFR-2, and MMP-2 levels were measured by Western blot using appropriate primary and secondary antibodies. Results: In the IUGR group, compared to the control group, there was a significantly lower level of Tie-1 (67.1% of controls, p p p = 0.001), and a significantly higher level of Tie-2 (119% of controls, p = 0.023). MMP-2 was increased in the IUGR group (127% of controls, p Conclusions: Placental levels of Tie-1, Tie-2, VEGFR-1, and VEGFR-2 are altered in pregnancies complicated by IUGR. Compared with that in normal pregnancies, the level of MMP-2 was upregulated. The present authors speculate that the results of this study represent the angiogenic imbalance observed in IUGR pregnancies; thereby resulting in poor and disturbed angiogenesis underlying delayed development of the fetus.

Slit2/Robo4 axis may contribute to endothelial cell dysfunction and angiogenesis disturbance in systemic sclerosis

ObjectiveIn systemic sclerosis (SSc), early microvascular injury is followed by impaired angiogenesis and peripheral capillary loss. Here, we investigated the possible contribution of the neurovascular guidance molecule Slit2 and its...

Modern View on Pathogenesis of Non Traumatic Osteonecrosis

Non traumatic osteonecrosis of the femoral head is one of the leading causes of hip function loss in young patients. At the late stages of this disease the only way to restore motor activity is total hip arthroplasty. Literature review presents the systematic analysis of the most significant causes of this disease (long-term intake of corticosteroids, alcohol abuse, thrombophilia). Pathogenetic mechanisms of femoral head vascularization disturbance are considered. In recent decades the fundamental genetic studies enabled to establish that pathogenesis of femoral head osteonecrosis is based on the polymorphisms of genes that ensure coagulation cascade, and angiogenesis disturbance.

Modern View on Pathogenesis of Non Traumatic Osteonecrosis

Non traumatic osteonecrosis of the femoral head is one of the leading causes of hip function loss in young patients. At the late stages of this disease the only way to restore motor activity is total hip arthroplasty. Literature review presents the systematic analysis of the most significant causes of this disease (long-term intake of corticosteroids, alcohol abuse, thrombophilia). Pathogenetic mechanisms of femoral head vascularization disturbance are considered. In recent decades the fundamental genetic studies enabled to establish that pathogenesis of femoral head osteonecrosis is based on the polymorphisms of genes that ensure coagulation cascade, and angiogenesis disturbance.

The role of endothelial cells in the vasculopathy of systemic sclerosis: A systematic review.

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by fibroproliferative vasculopathy, immunological abnormalities and progressive fibrosis of multiple organs including the skin. In this study, all English speaking articles concerning the role of endothelial cells (ECs) in SSc vasculopathy and representing biomarkers are systematically reviewed and categorized according to endothelial cell (EC) (dys)function in SSc. A sensitive search on behalf of the EULAR study group on microcirculation in Rheumatic Diseases was developed in Pubmed, The Cochrane Library and Web of Science to identify articles on SSc vasculopathy and the role of ECs using the following Mesh terms: (systemic sclerosis OR scleroderma) AND pathogenesis AND (endothelial cells OR marker). All selected papers were read and discussed by two independent reviewers. The selection process was based on title, abstract and full text level. Additionally, both reviewers further searched the reference lists of the articles selected for reading on full text level for supplementary papers. These additional articles went through the same selection process. In total 193 resulting articles were selected and the identified biomarkers were categorized according to description of EC (dys)function in SSc. The most representing and reliable biomarkers described by the selected articles were adhesion molecules for EC activation, anti-endothelial cell antibodies for EC apoptosis, vascular endothelial growth factor (VEGF), its receptor VEGFR-2 and endostatin for disturbed angiogenesis, endothelial progenitors cells for defective vasculogenesis, endothelin-1 for disturbed vascular tone control, Von Willebrand factor for coagulopathy and interleukin (IL)-33 for EC-immune system communication. Emerging, relatively new discovered biomarkers described in the selected articles, are VEGF165b, IL-17A and the adipocytokines. Finally, myofibroblasts involved in tissue fibrosis in SSc can derive from ECs or epithelial cells through a process known as endothelial-to-mesenchymal transition. This systematic review emphasizes the growing evidence that SSc is primarily a vascular disease where EC dysfunction is present and prominent in different aspects of cell survival (activation and apoptosis), angiogenesis and vasculogenesis and where disturbed interactions between ECs and various other cells contribute to SSc vasculopathy.

АНГИОГЕНЕЗ (ЛИТЕРАТУРНЫЙ ОБЗОР)

Aim. The aim of this study was to examine theoretical aspects of angiogenesis. Methods. The analysis of current literature and studies devoted to angiogenesis process. Results. The healthy body controls angiogenesis through a balance of modulators, regulated by a strong interaction between growth factors and inhibitors, the imbalance of which can lead to disease. These diseases are caused by both excessive angiogenesis (cancer, diabetic eye disease, rheumatoid arthritis), and insufficient angiogenesis (coronary heart disease, stroke, delayed wound healing). Also some perspective treatment modalities for these patients are revealed. Conclusion. Over one billion people worldwide suffer from diseases associated with disturbed angiogenesis. Comprehensive study of angiogenesis provides better understanding of the formation of new vessels in the healthy body and of pathogenic mechanisms, which can help in prevention or treatment of some diseases.

Pathophysiology of the disturbed angiogenesis in hemophilia

ABSTRACTIntroduction: It has been reported an increase of angiogenesis and vascular remodeling in hemophilic arthropathy. Therefore, antiangiogenic drugs could be useful in the management of hemophilic arthropathy. The aim of this review paper is to revise the role of angiogenesis in hemophilic arthropathy.Areas covered: This article is a narrative review of the pathophysiology of the disturbed angiogenesis in hemophilia and the potential role of antiangiogenic drugs in nonhemophilia patientsExpert commentary: Antiangiogenic drugs could be helpful in the future for the treatment of hemarthroses in hemophilic arthropathy. However, despite some recent reports emphasizing the role of angiogenesis in hemophilia, as these drugs have never been investigated for the treatment of hemophilic arthropathy in PWH, it is clear that they are not indicated.

Circulating angiopoietin-2 levels in children and adolescents with type 1 diabetes mellitus: relation to carotid and aortic intima-media thickness.

Angiopoietin-2 is a growth factor involved in the pathophysiology of vascular and inflammatory diseases such as arteriosclerosis. Carotid or aortic scans provide noninvasive screening tools for assessment of preclinical atherosclerosis in high-risk children. We assessed serum angiopoietin-2 in children and adolescents with type 1 diabetes mellitus as a potential marker for vascular complications in relation to glycemic control, inflammation and vascular structure. Sixty patients with type 1 diabetes were divided into 2 groups according to the presence of micro-vascular complications and compared with 30 healthy controls. High-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c), urinary albumin/creatinine ratio, serum angiopoietin-2, carotid and aortic intima-media thickness (CIMT and AIMT) were measured. CIMT, AIMT and serum angiopoietin-2 levels were significantly increased in patients with and without micro-vascular complications compared with controls, and the highest levels were in patients with complications (p<0.001). Angiopoietin-2 was higher in patients with microalbuminuria than normoalbuminuric group (p<0.001). Fasting blood glucose, HbA1c, hs-CRP, CIMT and AIMT were independently related to angiopoietin-2 in multiple regression analysis. Disease duration, hyperglycemia, poor glycemic control, hypercholesterolemia, inflammation and angiopoietin-2 were independent factors contributing to atherosclerosis risk. The relation between angiopoietin-2 and assessed parameters of vascular structure in type 1 diabetes reflects a state of endothelial injury and highlights the role of disturbed angiogenesis and vascular inflammation in the occurrence of diabetic complications.

LDL suppresses angiogenesis through disruption of the HIF pathway via NF-κB inhibition which is reversed by the proteasome inhibitor BSc2118.

Since disturbance of angiogenesis predisposes to ischemic injuries, attempts to promote angiogenesis have been made to improve clinical outcomes of patients with many ischemic disorders. While hypoxia inducible factors (HIFs) stimulate vascular remodeling and angiogenesis, hyperlipidemia impairs angiogenesis in response to various pro-angiogenic factors. However, it remains uncertain how HIFs regulate angiogenesis under hyperlipidemia. Here, we report that exposure to low-density lipoprotein (LDL) suppressed in vitro angiogenesis of human brain microvascular endothelial cells. Whereas LDL exposure diminished expression of HIF-1α and HIF-2α induced by hypoxia, it inhibited DMOG- and TNFα-induced HIF-1α and HIF-2α expression in normoxia. Notably, in both hypoxia and normoxia, LDL markedly reduced expression of HIF-1β, a constitutively stable HIF subunit, an event associated with NF-κB inactivation. Moreover, knockdown of HIF-1β down-regulated HIF-1α and HIF-2α expression, in association with increased HIF-1α hydroxylation and 20S proteasome activity after LDL exposure. Significantly, the proteasome inhibitor BSc2118 prevented angiogenesis attenuation by LDL through restoring expression of HIFs. Together, these findings argue that HIF-1β might act as a novel cross-link between the HIF and NF-κB pathways in suppression of angiogenesis by LDL, while proteasome inhibitors might promote angiogenesis by reactivating this signaling cascade under hyperlipidemia.

Delayed cutaneous wound closure in HO-2 deficient mice despite normal HO-1 expression.

Impaired wound healing can lead to scarring, and aesthetical and functional problems. The cytoprotective haem oxygenase (HO) enzymes degrade haem into iron, biliverdin and carbon monoxide. HO-1 deficient mice suffer from chronic inflammatory stress and delayed cutaneous wound healing, while corneal wound healing in HO-2 deficient mice is impaired with exorbitant inflammation and absence of HO-1 expression. This study addresses the role of HO-2 in cutaneous excisional wound healing using HO-2 knockout (KO) mice. Here, we show that HO-2 deficiency also delays cutaneous wound closure compared to WT controls. In addition, we detected reduced collagen deposition and vessel density in the wounds of HO-2 KO mice compared to WT controls. Surprisingly, wound closure in HO-2 KO mice was accompanied by an inflammatory response comparable to WT mice. HO-1 induction in HO-2 deficient skin was also similar to WT controls and may explain this protection against exaggerated cutaneous inflammation but not the delayed wound closure. Proliferation and myofibroblast differentiation were similar in both two genotypes. Next, we screened for candidate genes to explain the observed delayed wound closure, and detected delayed gene and protein expression profiles of the chemokine (C-X-C) ligand-11 (CXCL-11) in wounds of HO-2 KO mice. Abnormal regulation of CXCL-11 has been linked to delayed wound healing and disturbed angiogenesis. However, whether aberrant CXCL-11 expression in HO-2 KO mice is caused by or is causing delayed wound healing needs to be further investigated.

The role of the CCN family of proteins in female reproduction.

The CCN family of proteins consists of six high homologous matricellular proteins which act predominantly by binding to heparin sulphate proteoglycan and a variety of integrins. Interestingly, CCN proteins are regulated by ovarian steroid hormones and are able to adapt to changes in oxygen concentration, which is a necessary condition for successful implantation. CCN1 is involved in processes of angiogenesis within reproductive systems, thereby potentially contributing to diseases such as endometriosis and disturbed angiogenesis in the placenta and fetus. In the ovary, CCN2 is the key factor for follicular development, ovulation and corpora luteal luteolysis, and its deletion leads to fertility defects. CCN1, CCN2 and CCN3 seem to be regulators for human trophoblast proliferation and migration, but with CCN2 acting as a counterweight. Alterations in the expression of these three proteins could contribute to the shallow invasion properties observed in preeclampsia. Little is known about the role of CCN4-6 in the reproductive organs. The ability of CCN1, CCN2 and CCN3 to interact with numerous receptors enables them to adapt their biological function rapidly to the continuous remodelling of the reproductive organs and in the development of the placenta. The CCN proteins mediate their specific cell physiological function through the receptor type of their binding partner followed by a defined signalling cascade. Because of their partly overlapping expression patterns, they could act in a concert synergistically or in an opposite way within the reproductive organs. Imbalances in their expression levels are correlated to different human reproductive diseases, such as endometriosis and preeclampsia.

SDF-1 restores angiogenesis synergistically with VEGF upon LDL exposure despite CXCR4 internalization and degradation

Angiogenesis is compromised under conditions of hypercholesterolaemia. Since disturbed angiogenesis predisposes to ischaemic injuries, efforts have been made to promote angiogenesis by delivery of growth factors. How stromal cell-derived growth factor (SDF)-1 influences angiogenesis under conditions reflecting hypercholesterolaemia was unknown. We investigated the effects of SDF-1, administered alone or in combination with vascular endothelial growth factor (VEGF), on angiogenesis using proliferation, transwell migration, and Matrigel-based tube formation assays with human umbilical vein endothelial cells that were exposed to low-density lipoprotein (LDL). We observed that SDF-1 dose-dependently enhanced angiogenesis, but only partly reversed the LDL-mediated suppression of angiogenesis. Reduced abundance of SDF-1's receptor, CXCR4, was noted on the surface of LDL-exposed endothelial cells. In subcellular localization studies combined with pharmacological experiments, we showed that the loss of CXCR4 resulted from its internalization and degradation. SDF-1 synergistically increased angiogenesis when combined with VEGF. As a consequence, angiogenesis was fully restored. SDF-1 reduced oxidized LDL formation and increased the anti-oxidant capacity of endothelial cells, most strongly when administered together with VEGF. Combination therapies of growth factors, specifically SDF-1 and VEGF, might enhance angiogenesis more successfully than monotherapies under conditions of hypercholesterolaemia.