Endometriosis affects 10-15% of women and is associated with pelvic pain and infertility. Angiogenesis plays an essential role in its pathogenesis. Dendritic cells (DCs) were recently implicated in supporting tumor angiogenesis. As both tumors and endometriosis lesions depend on angiogenesis, we investigated the possibility that DCs may also play a role in endometriosis. We induced endometriosis in 8-wk-old female C57BL/6 mice by implantation of autologous endometrium into the peritoneal cavity. We observed an abundance of CD11c(+) DCs infiltrating sites of angiogenesis in endometriosis lesions. We noticed a similar pattern of infiltrating DCs at sites of angiogenesis in the peritoneal Lewis lung carcinoma tumor model. These DCs were immature (major histocompatability complex class II(low)) and expressed vascular endothelial growth factor receptor 2. Peritoneal implanted bone marrow-derived DCs (BMDCs) incorporated into both endometriosis lesions and into B16 melanoma tumors and enhanced their growth at 8 days compared with controls (5.1+/-2.5 vs. 1.5+/-0.5 mm(2), n=4 and 4, P<0.0001 for endometriosis; 67.6+/-15.1 vs. 22.7+/-14.6 mm(2), n=5 and 7, P=0.0004 for mouse melanoma). Finally, immature BMDCs but not mature BMDCs enhanced microvascular endothelial cell migration in vitro (219+/-51 vs. 93+/-32 cells, P=0.02). Based on these findings, we suggest a novel role for DCs in supporting angiogenesis and promoting lesion growth both in endometriosis and in tumors.
Myocardial infarction (MI) remains the leading cause of death in the western world. Although medical advancements have been made in interventional revascularization technologies, a large percentage of patients are not candidates for them due to co-morbidities or lack of local resources. Thus, there remains a need for the development of novel non-invasive strategies to treat MI. Approaches to accelerate revascularization within ischemic tissues through angiogenesis by providing Vascular Endothelial Growth Factor (VEGF) in protein or gene form has been shown to be effective in animal models but not in humans likely due to its short half-life and systemic toxicity. We previously showed that a small peptide (PR1P) we developed stabilizes VEGF in its active dimer state, increases VEGF binding to its receptors and potentiates VEGF activity. Here we show that systemic PR1P treatment targeted, stabilized and upregulated endogenous VEGF within ischemic myocardium following left coronary artery surgery in mice and rats. Targeted VEGF upregulation led to augmentation of heart function at two weeks following surgery. We conclude that PR1P is a potential candidate therapeutic for MI.
Background: Mechanical stretch has been shown to induce vascular remodeling and increase vessel density, but the pathophysiologic mechanisms and the morphologic changes induced by tensile forces to dermal vessels are poorly understood. Methods: A custom computer-controlled stretch device was designed and applied to the backs of C57BL/6 mice (n = 38). Dermal and vascular remodeling was studied over a 7-day period. Corrosion casting and three-dimensional scanning electron microscopy and CD31 staining were performed to analyze microvessel morphology. Hypoxia was assessed by immunohistochemistry. Western blot analysis of vascular endothelial growth factor (VEGF) and mRNA expression of VEGF receptors was performed. Results: Skin stretching was associated with increased angiogenesis as demonstrated by CD31 staining and vessel corrosion casting where intervascular distance and vessel diameter were decreased (p < 0.01). Immediately after stretching, VEGF dimers were increased. Messenger RNA expression of VEGF receptor 1, VEGF receptor 2, neuropilin 1, and neuropilin 2 was increased starting as early as 2 hours after stretching. Highly proliferating epidermal cells induced epidermal hypoxia starting at day 3 (p < 0.01). Conclusions: Identification of significant hypoxic cells occurred after identification of neovessels, suggesting an alternative mechanism. Increased expression of angiogenic receptors and stabilization of VEGF dimers may be involved in a mechanotransductive, prehypoxic induction of neovascularization.
The vascular endothelial growth factor (VEGF)-related factor, placental growth factor (PlGF),has been shown recently to play an important role in pathological VEGF-driven angiogenesis. In this study, we examine the effects of mPlGF/PlGF-2 overexpression in tumors grown from glioma cells containing a tetracycline-regulated mPlGF cDNA. Overexpression of mPlGF leads to increased tumor growth and vascular survival. When tetracycline is used to abruptly withdraw mPlGF overexpression, we see increased apoptosis in both vascular cells and macrophages. In addition, PlGF-2 induces survival gene expression and inhibits apoptosis in vitro. Thus, we propose that PlGF-2 contributes to tumor angiogenesis by providing increased survival function to endothelial cells and macrophages.
In Brief In vacuum assisted wound therapies, the establishment of a gradient in hypoxia and VEGF, the stabilization of VEGF dimers as well as the direct exertion of mechanical forces on wound cells leads to a directionalized sprouting of mature and functional vessels, a necessary condition for achieving improved wound healing.
Abstract Epidemiological studies have associated pigment production with protection against certain human diseases. In contrast to African Americans, European descendants are more likely to suffer from angiogenesis-dependent and inflammatory diseases, such as wet age-related macular degeneration (ARMD) and ulcerative colitis (UC), respectively. In this study, albino mice that produced high levels of fibromodulin (FMOD) developed less severe acute colitis compared with mice lacking in FMOD as assessed by clinical symptoms and histopathological changes. In a mouse model of dextran sodium sulfate (DSS)-induced acute colitis, FMOD depletion affected the expression and localization of tight junction proteins, contributing to the destruction of the epithelial barrier. Furthermore, this study revealed a stronger inflammatory response after DSS treatment in the absence of FMOD, where FMOD depletion led to an increase in activated T cells, plasmacytoid dendritic cells (pDCs), and type I IFN production. These findings point to FMOD as a potential biomarker of disease severity in UC among light-skinned individuals of European descent.
