Predictive value of the sFlt­1/PlGF ratio in women with suspected preeclampsia: An update (Review).

Preeclampsia (PE) is a major complication of pregnancy with an incidence rate of 2­8% and is a leading cause of maternal mortality and morbidity. The various consequences of severe preeclampsia for the fetus, neonate and child include intrauterine growth retardation (IUGR), fetal hypoxia, oligohydramnios, intrauterine fetal demise, increased perinatal mortality and morbidity, neurodevelopmental disorders and even irreversible brain damage (cerebral palsy). A number of studies have demonstrated that differences in maternal serum concentrations of angiogenic factors between preeclampsia and normotensive pregnancies can be used as biomarkers, either alone or in combination with other markers, to predict the development of PE. The presence in the maternal circulation of two proteins of placental origin, placental growth factor (PlGF) and soluble fms­like tyrosine kinase 1 (sFlt­1), has been shown to be of clinical value, as the sFlt­1/PlGF ratio appears to be the optimal predictive tool for the development of PE. The measurement of their concentration in maternal serum in screening models, serves as predictive marker for the development of PE or IUGR later in gestation. However, further research is required to improve its clinical applicability and provide guidelines for its use worldwide to achieve more consistent clinical management of women with PE.

Diclofenac, a NSAID, delays fracture healing in aged mice.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, belong to the most prescribed analgesic medication after traumatic injuries. However, there is accumulating evidence that NSAIDs impair fracture healing. Because bone regeneration in aged patients is subject to significant changes in cell differentiation and proliferation as well as a markedly altered pharmacological action of drugs, we herein analyzed the effects of diclofenac on bone healing in aged mice using a stable closed femoral facture model. Thirty-three mice (male n = 14, female n = 19) received a daily intraperitoneal injection of diclofenac (5 mg/kg body weight). Vehicle-treated mice (n = 29; male n = 13, female n = 16) served as controls. Fractured mice femora were analyzed by means of X-ray, biomechanics, micro computed tomography (µCT), histology and Western blotting. Biomechanical analyses revealed a significantly reduced bending stiffness in diclofenac-treated animals at 5 weeks after fracture when compared to vehicle-treated controls. Moreover, the callus tissue in diclofenac-treated aged animals exhibited a significantly reduced amount of bone tissue and higher amounts of fibrous tissue. Further histological analyses demonstrated less lamellar bone after diclofenac treatment, indicating a delay in callus remodeling. This was associated with a decreased number of osteoclasts and an increased expression of osteoprotegerin (OPG) during the early phase of fracture healing. These findings indicate that diclofenac delays fracture healing in aged mice by affecting osteogenic growth factor expression and bone formation as well as osteoclast activity and callus remodeling.

Tim-3 Coordinates Macrophage-Trophoblast Crosstalk via Angiogenic Growth Factors to Promote Pregnancy Maintenance.

T-cell immunoglobulin mucin-3 (Tim-3) is an important checkpoint that induces maternal-fetal tolerance in pregnancy. Macrophages (Mφs) play essential roles in maintaining maternal-fetal tolerance, remodeling spiral arteries, and regulating trophoblast biological behaviors. In the present study, the formation of the labyrinth zone showed striking defects in pregnant mice treated with Tim-3 neutralizing antibodies. The adoptive transfer of Tim-3+Mφs, rather than Tim-3-Mφs, reversed the murine placental dysplasia resulting from Mφ depletion. With the higher production of angiogenic growth factors (AGFs, including PDGF-AA, TGF-α, and VEGF), Tim-3+dMφs were more beneficial in promoting the invasion and tube formation ability of trophoblasts. The blockade of AGFs in Tim-3+Mφs led to the narrowing of the labyrinthine layer of the placenta, compromising maternal-fetal tolerance, and increasing the risk of fetal loss. Meanwhile, the AGFs-treated Tim-3-Mφs could resolve the placental dysplasia and fetal loss resulting from Mφ depletion. These findings emphasized the vital roles of Tim-3 in coordinating Mφs-extravillous trophoblasts interaction via AGFs to promote pregnancy maintenance and in extending the role of checkpoint signaling in placental development. The results obtained in our study also firmly demonstrated that careful consideration of reproductive safety should be taken when selecting immune checkpoint and AGF blockade therapies in real-world clinical care.

VEGF and fgf-2 released in palatal suture after rapid maxillary expansion (RME)

Abstract Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) have the ability to increase vascular proliferation and permeability. The aim of this study was to quantify the release of two diffusible angiogenic growth factors (VEGF and FGF-2) after rapid maxillary expansion (RME). Thirty animals were randomly assigned to two groups. Control group (5 rats - intact suture) and Experimental groups (25 rats with RME) which were evaluated in different periods of treatment. Five animals were euthanized in different periods of healing at 0, 1, 2, 3, 5 and 7 days after RME. RT-PCR was used to evaluate the gene expression of angiogenic growth factors released on different periods of study. Data were submitted to statistical analysis using ANOVA followed by Tukey test and significance was assumed at a=0.05. RT-PCR showed that mRNAs of VEGF and FGF-2 were expressed in intact palatal suture tissue. mRNAs of VEGF and FGF-2 was upregulated in early periods (24 h) after RME (p<0.001 and p<0.01, respectively). The molecular levels of VEGF never returned to its original baseline values, and FGF-2 expression decreased up to day 5 (p<0.001) and suddenly increased at day 7, returning to its original level. RME increased VEGF secretion, but decreased FGF-2 secretion when compared to intact tissue. The results showed that these angiogenic growth factors are released and regulated in the palatal suture tissue after RME and could make an important contribution to the knowledge of overall reparative response of the suture tissue during the bone remodeling process.

Resumo Fator de crescimento endothelial (VEGF) e fator de crescimento de fibroblasto (FGF-2) tem a capacidade de aumentar a proliferação e permeabilidade vascular. O objetivo deste estudo foi quantificar a liberação dos dois fatores de crescimento (VEGF e FGF-2) após expansão rápida da maxilla (ERM). Trinta animais foram divididos aleatoriamente em dois grupos. Grupo Controle (5 ratos - sutura intacta) e grupos Experimentais (25 ratos submetidos a ERM) que foram avaliados em períodos diferentes de tratamento. Cinco animais foram eutanaziados em diferentes períodos de avaliação aos 0, 2, 3, 5 e 7 dias após ERM. RT-PCR foi usado para avaliar a expressão gênica dos fatores de crescimento liberados nos diferentes períodos de estudo. Os dados foram submetidos à análise estatística usando ANOVA seguido do pós-teste de Tukey com nível de significância de a=0.05. RT-PCR mostrou que os RNAm de VEGF e FGF-2 estavam expressos na sutura palatina mediana intacta. Os RNAm de VEGF e FGF-2 foram estimulados nos períodos iniciais (24h) após ERM (p<0.001 e p<0.01, respectivamente). Os nívies moleculares de VEGF nunca retornaram aos valores originais, e a expressão de FGF-2 reduziu até o dia 5 (p<0.001) e de repente aumentou até o dia 7, retornando aos níveis originais. ERM aumentou a secreção de VEGF, mas diminuiu a secreção de FGF-2 quando comparado ao tecido intacto. Os resultados mostraram que estes fatores de crescimento são liberados e regulados na sutura palatina mediana após ERM e podem ser de importante contribuição para o entendimento da resposta reparadora geral do tecido da sutura durante o processo de remodelação óssea.

Combined Use of Detergents and Ultrasonication for Generation of an Acellular Pig Larynx.

The larynx is a fairly complex organ comprised of different muscles, cartilages, mucosal membrane, and nerves. Larynx cancer is generally the most common type of head and neck cancer. Treatment options are limited in patients with total or partial laryngectomy. Tissue-engineered organs have shown to be a promising alternative treatment for patients with laryngectomy. In this report we present an alternative and simple procedure to construct a whole pig larynx scaffold consisting of complete acellular structures of integrated muscle and cartilage. Larynges were decellularized (DC) using perfusion-agitation with detergents coupled with ultrasonication. DC larynges were then characterized to investigate the extracellular matrix (ECM) proteins, residual DNA, angiogenic growth factors, and morphological and ultrastructural changes to ECM fibers. After 17 decellularization cycles, no cells were observed in all areas of the larynx as confirmed by hematoxylin and eosin and DAPI (4',6-diamidino-2-phenylindole) staining. However, DC structures of dense thyroid and cricoid cartilage showed remnants of cells. All structures of DC larynges (epiglottis [p < 0.0001], muscle [p < 0.0001], trachea [p = 0.0045], and esophagus [p = 0.0008]) showed DNA <50 ng/mg compared with native larynx. Immunohistochemistry, Masson's trichrome staining, and Luminex analyses showed preservation of important ECM proteins and angiogenic growth factors in DC larynges. Compared with other growth factors, mostly retained growth factors in DC epiglottis, thyroid muscle, and trachea include granulocyte colony-stimulating factor, Leptin, fibroblast growth factor-1, Follistatin, hepatocyte growth factor, and vascular endothelial growth factor-A. Scanning electron microscopy and transmission electron microscopy analysis confirmed the structural arrangements of ECM fibers in larynges to be well preserved after DC. Our findings suggest that larynges can be effectively DC using detergent ultrasonication. ECM proteins and angiogenic growth factors appear to be better preserved using this method when compared with the native structures of larynges. This alternative DC method could be helpful in building scaffolds from dense tissue structures such as cartilage, tendon, larynx, or trachea for future in vitro recellularization studies or in vivo implantation studies in the clinic.

Therapeutic Angiogenesis by a "Dynamic Duo": Simultaneous Expression of HGF and VEGF165 by Novel Bicistronic Plasmid Restores Blood Flow in Ischemic Skeletal Muscle.

Therapeutic angiogenesis is a promising strategy for relief of ischemic conditions, and gene delivery was used to stimulate blood vessels' formation and growth. We have previously shown that intramuscular injection of a mixture containing plasmids encoding vascular endothelial growth factor (VEGF)165 and hepatocyte growth factor (HGF) leads to restoration of blood flow in mouse ischemic limb, and efficacy of combined delivery was superior to each plasmid administered alone. In this work, we evaluated different approaches for co-expression of HGF and VEGF165 genes in a panel of candidate plasmid DNAs (pDNAs) with internal ribosome entry sites (IRESs), a bidirectional promoter or two independent promoters for each gene of interest. Studies in HEK293T culture showed that all plasmids provided synthesis of HGF and VEGF165 proteins and stimulated capillary formation by human umbilical vein endothelial cells (HUVEC), indicating the biological potency of expressed factors. Tests in skeletal muscle explants showed a dramatic difference and most plasmids failed to express HGF and VEGF165 in a significant quantity. However, a bicistronic plasmid with two independent promoters (cytomegalovirus (CMV) for HGF and chicken b-actin (CAG) for VEGF165) provided expression of both grow factors in skeletal muscle at an equimolar ratio. Efficacy tests of bicistronic plasmid were performed in a mouse model of hind limb ischemia. Intramuscular administration of plasmid induced significant restoration of perfusion compared to an empty vector and saline. These findings were supported by increased CD31+ capillary density in animals that received pHGF/VEGF. Overall, our study reports a first-in-class candidate gene therapy drug to deliver two pivotal angiogenic growth factors (HGF and VEGF165) with properties that provide basis for future development of treatment for an unmet medical need-peripheral artery disease and associated limb ischemia.

Angiogenesis Inhibition in Prostate Cancer: An Update.

Prostate cancer (PCa), like all other solid tumors, relies on angiogenesis for growth, progression, and the dissemination of tumor cells to other parts of the body. Despite data from in vitro and in vivo preclinical studies, as well as human specimen studies indicating the crucial role played by angiogenesis in PCa, angiogenesis inhibition in clinical settings has not shown significant benefits to patients, thus challenging the inclusion and usefulness of antiangiogenic agents for the treatment of PCa. However, one of the apparent reasons why these antiangiogenic agents failed to meet expectations in PCa can be due to the choice of the antiangiogenic agents, because the majority of these drugs target vascular endothelial growth factor-A (VEGFA) and its receptors. The other relevant causes might be inappropriate drug combinations, the duration of treatment, and the method of endpoint determination. In this review, we will first discuss the role of angiogenesis in PCa growth and progression. We will then summarize the different angiogenic growth factors that influence PCa growth dynamics and review the outcomes of clinical trials conducted with antiangiogenic agents in PCa patients and, finally, critically assess the current status and fate of antiangiogenic therapy in this disease.

The impact of intercellular communication for the generation of complex multicellular prevascularized tissue equivalents.

In reconstructive surgery the use of prevascularized soft tissue equivalents is a promising approach for wound coverage of defects after tumor resection or trauma. However, in previous studies to generate soft tissue equivalents on collagen membranes, microcapillaries were restricted to superficial areas. In this study, to understand which factors were involved in the formation of these microcapillaries, the levels of the angiogenic factors vascular endothelial growth factor (VEGF), Interleukin-8 (IL-8), and basic fibroblast growth factor (bFGF) in the supernatants of the tissue equivalents were examined at various time points and conditions. Additionally, the influence of these factors on viability, proliferation, migration, and tube formation in monocultures compared to cocultures of fibroblast and endothelial cells was examined. The results showed that VEGF production was decreased in cocultures compared to fibroblast monocultures and the lowest VEGF levels were observed in endothelial cell monocultures. Additionally, the highest levels of IL-8 were observed in cocultures compared to monocultures. Similar results were observed for bFGF with lowest levels seen within the first 24 hr and highest levels in cocultures. VEGF and IL-8 were shown to promote endothelial cell viability, proliferation and migration and angiogenic parameters such as tube density, total tube length, and number of tube branches. Addition of VEGF and IL-8 to cocultures resulted in accelerated and denser formation of capillary-like structures. The results indicate that VEGF, IL-8, and bFGF strongly influence cellular behavior of endothelial cells and this information should be useful in promoting the formation of microcapillary-like structures in complex tissue equivalents.

Prevascularized mesenchymal stem cell-sheets increase survival of random skin flaps in a nude mouse model.

A random skin flap is commonly applied in plastic and reconstructive surgery. The distal part of the random skin flap often risks necrosis because the blood flow may be compromised. Prevascularization is a widely used technology to intensify the vascularization function of biomaterials. In fact, human mesenchymal stem cell (hMSC) sheets promote neoangiogenesis. We speculated that prevascularized hMSC cell sheets (PHCS) would further improve neovascularization by producing more angiogenic growth factors in a random skin flap animal model. In this study, PHCS were set up by co-culturing human umbilical vein endothelial cells (HUVECs) with hMSC cell sheets (HCS). In vitro, we observed microvessel formation and significantly increased production of angiogenesis-related factors. Thus, we analyzed the microvessel networks, vascular maturation, and angiogenic growth factors of the cell sheet. In vivo, PHCS and HCS were implanted in a murine ischemic random skin flap model. Implanted PHCS significantly increased blood perfusion and improved skin flap survival when compared to untreated control skin flaps. The survival rate of the prevascularized and control skin flaps was assessed after 3, 5, and 7 days via analysis of macroscopic images and Laser Doppler Perfusion Imaging (LDPI). Additionally, the numbers of skin appendages, collagen fibers deposition, and epidermal thickness were evaluated. Moreover, the PHCS group also induced the most intense neovascularization, the upshot of which was a robust blood microcirculation supporting skin flap survival. Therefore, PHCS implantation can effectively enhance local neoangiogenesis and hence increase the survival of otherwise ischemic skin flaps. Hence, local administration of PHCS may serve as an alternative approach in improving random skin flap survival.

Phenotypic differences in early outgrowth angiogenic cells based on in vitro cultivation.

Bone marrow-derived early outgrowth cells play an important role in endothelial repair. In vitro isolation techniques have identified two distinct morphological early outgrowth cell populations, but it is still unknown whether they present some functional phenotypic differences. Accordingly, the aim of the present study was to determine whether there are phenotypic differences in cellular function between two putative early outgrowth cells in culture. Peripheral blood samples were collected from 18 healthy adults. Thereafter, mononuclear cells were isolated by Ficoll density-gradient centrifugation and plated on 6-well plates coated with human fibronectin. After 2 and 7 days, respectively, non-adherent cells (NAC) and adherent cells (AC) underwent functional assays in order to measure the migratory capacity (Boyden chamber), angiogenic growth factor release (ELISA) and apoptosis (TUNEL). Migration to both VEGF (517 ± 74 vs. 273 ± 74 AU) and SDF-1 (517 ± 68 vs. 232 ± 68 AU) were approximately twofold higher (P < 0.05) in the NAC when compared to AC. Release of angiogenic factors, granulocyte colony-stimulating and hepatocyte growth factor, were not different between cell types. Apoptotic response to staurosporine was significantly lower in NAC (20 ± 32 vs. 125 ± 32%). In summary, NAC and AC demonstrated functional phenotypic differences in migratory capacity and apoptotic susceptibility, which makes it difficult to compare these two early outgrowth cell populations in literature.

BPC 157 and Standard Angiogenic Growth Factors. Gastrointestinal Tract Healing, Lessons from Tendon, Ligament, Muscle and Bone Healing.

Commonly, the angiogenic growth factors signify healing. However, gastrointestinal ulceration is still poorly understood particularly with respect to a general pharmacological/pathophysiological role of various angiogenic growth factors implemented in growth factors wound healing concept. Thereby, we focused on the stable gastric pentadecapeptide BPC 157, a peptide given always alone vs. standard peptidergic angiogenic growth factors (EGF, FGF, VEGF), and numerous carriers. Further, we reviewed how the gastrointestinal tract healing could be generally perceived (i) in terms of angiogenic growth factors, and/or (ii) through the healing of extragastrointestinal tissues healing, such as tendon, ligament, muscle and bone, and vice versa. Respected were the beneficial effects obtained with free peptides or peptides with different carriers; EGF, FGF, VEGF, and BPC 157, their presentation along with injuries, and a healing commonality, providing their implementation in both gastrointestinal ulcer healing and tendon, ligament, muscle and bone healing. Only BPC 157 was consistently effective in all of the models of acute/chronic injury of esophagus, stomach, duodenum and lower gastrointestinal tract, intraperitoneally, per-orally or locally. Unlike bFGF-, EGF-, VEGF-gastrointestinal tract studies demonstrating improved healing, most of the studies on tendon, muscle and bone injuries provide evidence of their (increased) presentation along with the various procedures used to produce beneficial effects, compared to fewer studies in vitro, while in vivo healing has a limited number of studies, commonly limited to local application, diverse healing evidence with diverse carriers and delivery systems. Contrary to this, BPC 157 - using same regimens like in gastrointestinal healing studies - improves tendon, ligament and bone healing, accurately implementing its own angiogenic effect in the healing. Thus, we claim that just BPC 157 represents in practice a pharmacological and pathophysiological role of various peptidergic growth factors.

Correlation between increasing tissue ischemia and circulating levels of angiogenic growth factors in peripheral artery disease.

INTRODUCTION: The aim of the present study was to assess the circulating levels of vascular endothelial growth factor (VEGF) and other suggested therapeutic growth factors with the degree of ischemia in patients with different clinical manifestations of peripheral arterial disease (PAD) according to the Rutherford grades. METHODS: The study cohort consists of 226 consecutive patients admitted to a Department of Vascular Surgery for elective invasive procedures. PAD patients were grouped according to the Rutherford grades after a clinical assessment. Ankle-brachial pressure indices (ABI) and absolute toe pressure (TP) values were measured. Serum levels of circulating VEGF, hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF) were measured from serum and analysed against Rutherford grades and peripheral hemodynamic measurements. RESULTS: The levels of VEGF (P = 0.009) and HGF (P < 0.001) increased significantly as the ischaemic burden became more severe according to the Rutherford grades. PDGF behaved in opposite manner and declined along increasing Rutherford grades (P = 0.004). A significant, inverse correlations between Rutherford grades was detected as follows; VEGF (Pearson's correlation = 0.183, P = 0.004), HGF (Pearson's correlation = 0.253, P < 0.001), bFGF (Pearson's correlation = 0.169, P = 0.008) and PDGF (Pearson's correlation = 0.296, P < 0.001). In addition, VEGF had a clear direct negative correlation with ABI (Pearson's correlation -0.19, P = 0.009) and TP (Pearson's correlation -0.20, P = 0.005) measurements. CONCLUSIONS: Our present observations show that the circulating levels of VEGF and other suggested therapeutic growth factors are significantly increased along with increasing ischemia. These findings present a new perspective to anticipated positive effects of gene therapies utilizing VEGF, HGF, and bFGF, because the levels of these growth factors are endogenously high in end-stage PAD.

Glomeruloid Microvascular Proliferation, Desmoplasia, and High Proliferative Index as Potential Indicators of High Grade Canine Choroid Plexus Tumors.

Choroid plexus tumors (CPT) are intraventricular neoplasms accounting for 10% of all primary central nervous system tumors in dogs. They are frequently classified according to the human WHO classification into choroid plexus papilloma (CPP, grade I), atypical CPP (aCPP, grade II), and choroid plexus carcinoma (CPC, grade III). Histological features observed in canine CPT such as increased vascular density (IVD) and glomeruloid microvascular proliferation (GMVP) are not part of the WHO classification. This multi-centric study aimed to investigate tumor-associated vascular hyperplasia in dogs by determining the prevalence of GMVP and IVD in 52 canine CPT and their association with tumor grade. In addition, the expression of angiogenic factors was assessed by immunohistochemistry in 25 tumors to investigate the pathogenesis of tumor-associated vascular hyperplasia. Based on the classical histological hallmarks, this study of 52 CPT identified 22 (42%) CPP (grade I) and 30 of (58%) CPC (grade III). GMVP was more prevalent in CPC (13/30; 43%) than CPP (1/22; 4%), whereas IVD occurred to a similar extent in CPP and CPC. Desmoplasia was more common in CPC (19/30; 63%) than CPP (2/22; 9%), and similarly, the proliferative index (PI) of neoplastic epithelium was significantly higher in CPC (5.14%) than CPP (0.94%). The majority of CPT expressed platelet-derived growth factor (PDGF), PDGFRα, PDGFRß, and vascular endothelial growth factor (VEGF) irrespective of tumor grade or tumor-associated vascular hyperplasia. These results suggest that tumor-associated GMVP, desmoplasia, and PI may serve as histological indicators of malignancy in CPT.

A placenta clinic approach to the diagnosis and management of fetal growth restriction.

Effective detection and management of fetal growth restriction is relevant to all obstetric care providers. Models of best practice to care for these patients and their families continue to evolve. Since much of the disease burden in fetal growth restriction originates in the placenta, the concept of a multidisciplinary placenta clinic program, managed primarily within a maternal-fetal medicine division, has gained popularity. In this context, fetal growth restriction is merely one of many placenta-related disorders that can benefit from an interdisciplinary approach, incorporating expertise from specialist perinatal ultrasound and magnetic resonance imaging, reproductive genetics, neonatal pediatrics, internal medicine subspecialties, perinatal pathology, and nursing. The accurate diagnosis and prognosis for women with fetal growth restriction is established by comprehensive clinical review and detailed sonographic evaluation of the fetus, combined with uterine artery Doppler and morphologic assessment of the placenta. Diagnostic accuracy for placenta-mediated fetal growth restriction may be enhanced by quantification of maternal serum biomarkers including placenta growth factor alone or combined with soluble fms-like tyrosine kinase-1. Uterine artery Doppler is typically abnormal in most instances of early-onset fetal growth restriction and is associated with coexistent preeclampsia and underlying maternal vascular malperfusion pathology of the placenta. By contrast, rare but potentially more serious underlying placental diagnoses, such as massive perivillous fibrinoid deposition, chronic histiocytic intervillositis, or fetal thrombotic vasculopathy, may be associated with normal uterine artery Doppler waveforms. Despite minor variations in placental size, shape, and cord insertion, placental function remains, largely normal in the general population. Consequently, morphologic assessment of the placenta is not currently incorporated into current screening programs for placental complications. However, placental ultrasound can be diagnostic in the context of fetal growth restriction, for example in Breus' mole and triploidy, which in turn may enhance diagnosis and management. Several examples are illustrated in our figures and supplementary videos. Recent advances in the ability of multiparameter screening and intervention programs to reduce the risk of severe preeclampsia will likely increase efforts to deliver similar improvements for women at risk of fetal growth restriction. Placental pathology is important because the underlying pathologies associated with fetal growth restriction have a wide range of recurrence risks. Rare conditions such as massive perivillous fibrinoid deposition or chronic histolytic intervillositis may recur in >50% of subsequent pregnancies. Postpartum care in a placenta-focused program can provide effective counseling for modifiable maternal risk factors, and can assist in planning future pregnancy care based on the pathologic basis of fetal growth restriction.

Angiogenic Growth Factors for Coronary Artery Disease: Current Status and Prospects.

Although there have been advances in coronary artery bypass grafting and percutaneous coronary intervention, some patients who have ischemic coronary artery disease (CAD) are ineligible for revascularization due to suboptimal anatomy. Cardiac angiogenesis is not only a physiological response to ischemia or hypoxia but also a potential target of therapeutic strategies. Preclinical studies have shown a great enthusiasm on therapeutic angiogenesis for ischemic CAD. However, the latest trials provided the limited evidence on its efficacy. This article aims to discuss the physiological process of angiogenesis, the characteristic of angiogenic growth factors, delivery system, and clinical and preclinical studies, which can provide a novel insight into the therapeutic angiogenesis for CAD.

Porcine Bone Scaffolds Adsorb Growth Factors Secreted by MSCs and Improve Bone Tissue Repair.

An ideal tissue-engineered bone graft should have both excellent pro-osteogenesis and pro-angiogenesis properties to rapidly realize the bone regeneration in vivo. To meet this goal, in this work a porcine bone scaffold was successfully used as a Trojan horse to store growth factors produced by mesenchymal stem cells (MSCs). This new scaffold showed a time-dependent release of bioactive growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), in vitro. The biological effect of the growth factors-adsorbed scaffold on the in vitro commitment of MSCs into osteogenic and endothelial cell phenotypes has been evaluated. In addition, we have investigated the activity of growth factor-impregnated granules in the repair of critical-size defects in rat calvaria by means of histological, immunohistochemical, and molecular biology analyses. Based on the results of our work bone tissue formation and markers for bone and vascularization were significantly increased by the growth factor-enriched bone granules after implantation. This suggests that the controlled release of active growth factors from porcine bone granules can enhance and promote bone regeneration.

Pro-Angiogenesis Therapy and Aging: A Mini-Review.

Apart from major illnesses and chronic afflictions, the elderly experience lesser ailments, such as muscle weakness, cold intolerance, and transient memory lapses. Physical signs in the aged include wrinkled skin and the slow healing of skin abrasions. These ailments and signs are grouped together because they may be due in part to an age-linked, waning microcirculation. A reduced capillary density (CD) throughout the body of aged people and animals has been reported in over 40 papers. The reduced CD is due in turn to declining levels of angiogenic growth factors (AGFs) throughout the body during old age, as documented in 7 reports in the literature. From this perspective, old age is a deficiency state of AGFs, much like the reduced testosterone levels in elderly males. The above data on reduced CD and AGFs are the basis for the "angiogenesis hypothesis of aging", whose corollary suggests pro-angiogenesis therapy for symptoms and signs of old age. Several AGFs are now available in recombinant forms (e.g., vascular endothelial growth factor) and have been used safely in animal experiments and in short-term clinical trials.

Angiogenic growth factors in myocardial infarction: a critical appraisal.

In the recent past, substantial advances have been made in the treatment of myocardial infarction (MI). Despite the impact of these positive developments, MI remains to be a leading cause of morbidity as well as mortality. An interesting hypothesis is that the development of new blood vessels (angiogenesis) or the remodeling of preexisting collaterals may form natural bypasses that could compensate for the occlusion of an epicardial coronary artery. A number of angiogenic factors are proven to be elicited during MI. Exogenous supplementation of these growth factors either in the form of recombinant protein or gene would enhance the collateral vessel formation and thereby improve the outcome after MI. The aim of this review is to describe the nature and potentials of different angiogenic factors, their expression, their efficacy in animal studies, and clinical trials pertaining to MI.

"Stress" is 80 Years Old: From Hans Selye Original Paper in 1936 to Recent Advances in GI Ulceration.

The first scientific publication on 'general adaption syndrome', or as we know today 'biologic stress' has been published in Nature in 1936 by the 29-year old Hans Selye. His results in that short publication that contained no references or illustrations, were based on experiments in rats that were exposed to severe insults/ stressors, but his idea about a 'nonspecific bodily response' originated from his observations of sick patients whom he had seen as a medical student and young clinician. Autopsy of stressed rats revealed three major, grossly visible changes: hyperemia and enlargement of the adrenals, atrophy of the thymus and lymph nodes as well as hemorrhagic gastric erosions/ulcers (the "stress triad"). Based on this and additional observations, he concluded that the key master organ in stress reactions is the adrenal cortex (although he also accepted the limited and short lasting effect of catecholamines released from the adrenal medulla) which stimulated by an increased secretion of ACTH, secreted by the anterior pituitary gland. He thus identified the first molecular mediators of the stress reaction, i.e., steroids released from the adrenal cortex that we call today glucocorticoids, based on his classification and naming of steroids. At the end of a very productive life in experimental medicine, Selye recognized that under both unpleasant and demanding stressors as well as positive, rewarding stimuli adrenal cortex releases the same glucocorticoids and only certain brain structures may distinguish the stimuli under distress and eustress - terms he introduced in 1974, that also contained his last definition of stress: the nonspecific response of the body on any demand on it. After brief description of the history of stress research, the rest of this review is focused on one element of stress triad, i.e., gastroduodenal ulceration, especially its pathogenesis, prevention and treatment. Following a short description of acute gastroprotection, discovered by one of Selye's students, we discuss new molecular mediators of gastroduodenal ulceration like dopamine and new drugs that either only heal (very potently, on molar basis) or prevent and heal ulcers like sucralfate derivatives and the relatively new peptide BPC-157. We conclude that despite the extensive and multidisciplinary research on stress during the last 80 years, a lot of basic and clinical research is needed to better understand the manifestations, central and peripheral molecular regulators of stress response, especially the modes of prevention/management of distress or its transformation into eustress and the treatment of stress-related diseases.