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Lymphangiogenesis-independent resolution of experimental edema.

ABSTRACT: Vascular endothelial growth factor (VEGF)-C is necessary for lymphangiogenesis, and excess VEGF-C has been shown to be ameliorative for edema produced by lymphatic obstruction in experimental models. However, it has recently been shown that edema can resolve in the mouse tail even in the complete absence of capillary lymphangiogenesis when distal lymph fluid crosses the regenerating wound site interstitially. This finding has raised questions about the action of VEGF-C/VEGF receptor (VEGFR) signaling during the resolution of experimental edema. Here, the roles of VEGFR-2 and VEGFR-3 signaling in edema resolution were explored. It was found that edema resolved following neutralization of either VEGFR-2 or VEGFR-3 in the mouse tail skin, which inhibited lymphangiogenesis. Neutralization of either VEGFR-2 or VEGFR-3 reduced angiogenesis at the site of obstruction at day 10 (9.2 +/- 1.2% and 11.5 +/- 1.0% blood capillary coverage, respectively) relative to controls (14.3 +/- 1.5% blood capillary coverage). Combined VEGFR-2/-3 neutralization more strongly inhibited angiogenesis (6.9 +/- 1.5% blood capillary coverage), leading to a reduced wound repair of the lymphatic obstruction and extended edema in the tail skin. In contrast, improved tissue repair of the obstruction site increased edema resolution. Macrophages in the swollen tissue were excluded as contributing factors in the VEGFR-dependent extended edema. These results support a role for VEGFR-2/-3-combined signaling in the resolution of experimental edema that is lymphangiogenesis independent.

SUBMITTER: Ongstad EL

PROVIDER: S-EPMC2904140 | biostudies-other | 2010 Jul

REPOSITORIES: biostudies-other

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Lymphangiogenesis-independent resolution of experimental edema.

Ongstad Emily L EL Bouta Echoe M EM Roberts Jaclynn E JE Uzarski Joseph S JS Gibbs Sara E SE Sabel Michael S MS Cimmino Vincent M VM Roberts Melissa A MA Goldman Jeremy J

American journal of physiology. Heart and circulatory physiology 20100305 1

Vascular endothelial growth factor (VEGF)-C is necessary for lymphangiogenesis, and excess VEGF-C has been shown to be ameliorative for edema produced by lymphatic obstruction in experimental models. However, it has recently been shown that edema can resolve in the mouse tail even in the complete absence of capillary lymphangiogenesis when distal lymph fluid crosses the regenerating wound site interstitially. This finding has raised questions about the action of VEGF-C/VEGF receptor (VEGFR) sign ...[more]

PMID: 20207821

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Project description:Intestinal microbiota can modulate portal hypertension through the regulation of the intestinal vasculature. We have recently demonstrated that bacterial antigens activate Paneth cells (PCs) to secrete products that regulate angiogenesis and portal hypertension. In the present work we hypothesized that Paneth cells regulate the development of lymphatic vessels under the control of intestinal microbiota during experimental portal hypertension. We used a mouse model of inducible PCs depletion (Math1Lox/LoxVilCreERT2) and performed partial portal vein ligation (PPVL) to induce portal hypertension. After 14 days, we performed mRNA sequencing and evaluated the expression of specific lymphangiogenic genes in small intestinal tissue. Intestinal and mesenteric lymphatic vessels proliferation was assessed by immunohistochemistry. Intestinal organoids with or without PCs were exposed to pathogen-associated molecular patterns, and conditioned media (CM) was used to stimulate human lymphatic endothelial cells (LECs). The lymphangiogenic activity of stimulated LECs was assessed by tube formation and wound healing assays. Secretome analysis of CM was performed using label-free proteomics quantification methods. Intestinal immune cell infiltration was evaluated by immunohistochemistry. We observed that the intestinal gene expression pattern was altered by the absence of PCs only in portal hypertensive mice. We found a decreased expression of specific lymphangiogenic genes in the absence of PCs during portal hypertension, resulting in a reduced proliferation of intestinal and mesenteric lymphatic vessels as compared to controls. In vitro analyses demonstrated that lymphatic tube formation and endothelial wound healing responses were reduced significantly in LECs treated with CM from organoids without PCs. Secretome analyses of CM revealed that PCs secrete proteins that are involved in lipid metabolism, cell growth and proliferation. Additionally, intestinal macrophages infiltrated the ileal mucosa and submucosa of mice with and without Paneth cells in response to portal hypertension. Our results suggest that intestinal microbiota signals stimulate Paneth cells to secrete factors that modulate the intestinal and mesenteric lymphatic vessels network during experimental portal hypertension.

Project description:BACKGROUND: Vasogenic edema dynamically accumulates in many brain disorders associated with brain inflammation, with the critical step of edema exacerbation feared in patient care. Water entrance through blood-brain barrier (BBB) opening is thought to have a role in edema formation. Nevertheless, the mechanisms of edema resolution remain poorly understood. Because the water channel aquaporin 4 (AQP4) provides an important route for vasogenic edema resolution, we studied the time course of AQP4 expression to better understand its potential effect in countering the exacerbation of vasogenic edema. METHODS: Focal inflammation was induced in the rat brain by a lysolecithin injection and was evaluated at 1, 3, 7, 14 and 20 days using a combination of in vivo MRI with apparent diffusion coefficient (ADC) measurements used as a marker of water content, and molecular and histological approaches for the quantification of AQP4 expression. Markers of active inflammation (macrophages, BBB permeability, and interleukin-1?) and markers of scarring (gliosis) were also quantified. RESULTS: This animal model of brain inflammation demonstrated two phases of edema development: an initial edema build-up phase during active inflammation that peaked after 3 days (ADC increase) was followed by an edema resolution phase that lasted from 7 to 20 days post injection (ADC decrease) and was accompanied by glial scar formation. A moderate upregulation in AQP4 was observed during the build-up phase, but a much stronger transcriptional and translational level of AQP4 expression was observed during the secondary edema resolution phase. CONCLUSIONS: We conclude that a time lag in AQP4 expression occurs such that the more significant upregulation was achieved only after a delay period. This change in AQP4 expression appears to act as an important determinant in the exacerbation of edema, considering that AQP4 expression is insufficient to counter the water influx during the build-up phase, while the second more pronounced but delayed upregulation is involved in the resolution phase. A better pathophysiological understanding of edema exacerbation, which is observed in many clinical situations, is crucial in pursuing new therapeutic strategies.

Project description:ImportancePredicting the extent of corneal edema resolution after Descemet membrane endothelial keratoplasty (DMEK) may help in preoperative decision-making by identifying patients who may benefit from restoring endothelial function.ObjectiveTo develop and validate a predictive model for edema resolution after DMEK using Scheimpflug tomographic imaging.Design, setting, and participantsTwo prospective studies recruited participants with advanced Fuchs dystrophy at a university-based tertiary referral center between July 1, 2017, and August 31, 2019. Analyses were designed in November 2019 and completed on June 30, 2020. Development of a predictive model using linear least absolute shrinkage and selection operator regression was conducted in a derivation cohort (100 eyes). Overall performance, discrimination, and calibration were tested in the separate validation cohort (32 eyes).ExposuresPreoperative Scheimpflug parameters and patient-reported visual disability were considered as potential predictors of edema resolution: (1) tomographic features (irregularity of lines of equal corneal thickness, displacement of the thinnest point of corneal thickness from the inferior-temporal quadrant, and absolute amount of focal posterior corneal depression), (2) standardized anterior and posterior corneal backscatter, (3) preoperative central corneal thickness, and (4) Fuchs dystrophy-specific visual disability.Main outcomes and measuresDecrease in central corneal thickness after DMEK indicative of edema resolution.ResultsOf the 88 patients included in the analysis, 54 were women (61%); median age was 68 years (interquartile range [IQR], 59-76 years). A median of 13 months after DMEK (IQR, 9-16 months), median corneal thickness was 77 μm lower (IQR, 51-94 μm) in the derivation cohort and 75 μm lower in the validation cohort (IQR, 54-96 μm) than before surgery. Per 10-μm edema resolution, eyes gained 0.66 Early Treatment Diabetic Retinopathy Study letters (95% CI, 0.09-1.23) in best-corrected visual acuity. Three tomographic features were present in 68 of 100 eyes (68%) in the derivation cohort and in 18 of 32 eyes (56%) in the validation cohort before DMEK and in only 1 of 132 eyes (1%) after DMEK. To predict edema resolution after DMEK based on preoperative assessment, 5 variables were selected by the statistical learning algorithm: nonparallel isopachs, focal posterior depression, anterior and posterior corneal backscatter, and central corneal thickness. In the separate validation cohort, the model showed high overall performance, discrimination, and calibration.Conclusions and relevanceThese post hoc analyses of prospective cohorts support a model for use in the prediction of edema resolution after DMEK using Scheimpflug measurement to identify patients benefitting most from DMEK.

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Lymphangiogenesis-independent resolution of experimental edema.

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Lymphangiogenesis-independent resolution of experimental edema.

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