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Syndecan-2 selectively regulates VEGF-induced vascular permeability

Nature Cardiovascular Research volume 1, pages 518–528 (2022)Cite this article

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Abstract

Vascular endothelial growth factor (VEGF)-driven increase in vascular permeability is a key feature of many disease states associated with inflammation and ischemic injury, contributing significantly to morbidity and mortality in these settings. Despite its importance, no specific regulators that preferentially control a VEGF-dependent increase in permeability versus its other biological activities have been identified. Here, we report that a proteoglycan, Syndecan-2 (Sdc2), regulates the interaction between a transmembrane phosphatase, DEP1, and VEGFR2 by controlling cell surface levels of DEP1. In the absence of Sdc2 or the presence of an antibody that blocks the Sdc2–DEP1 interaction, increased plasma membrane DEP1 levels promote selective dephosphorylation of the VEGFR2 Y951 site that is involved in permeability control. Either an endothelial-specific Sdc2 deletion or a treatment with an anti-Sdc2 antibody results in a marked reduction in stroke size due to a decrease in intracerebral edema.

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Fig. 1: Sdc2 deletion leads to reduced VEGFA-induced Y951 phosphorylation and permeability in vivo.
Fig. 2: Increased DEP1 surface level in Sdc2−/− mouse ECs promotes selective dephosphorylation of VEGFR2 Y951 (Y951 in mouse).
Fig. 3: Sdc2–DEP1 interaction regulates DEP1 surface level and can be exploited to achieve specific inhibition of VEGFA-induced permeability.
Fig. 4: Sdc2 deletion or treatment with an antibody that blocks the Sdc2–DEP1 interaction confers neuroprotection in a mouse focal stroke model.
Fig. 5: Proposed working model for regulation of DEP1 surface level by Sdc2.

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All data supporting the findings of this study are available within the paper and associated files. Source data are provided with this paper.

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Acknowledgements

We thank D. Chen for the technical assistance and helpful discussion regarding the corneal pocket assay and confocal imaging. This work was supported by grants from National Institute of Health (NIH) HL149343 and HL062289 to Michael Simons.

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Authors and Affiliations

  1. Yale Cardiovascular Research Center Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA

    F. Corti, E. Ristori, J. Zhang, Z. W. Zhuang & M. Simons

  2. Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA

    F. Rivera-Molina & D. Toomre

  3. Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA

    J. Mihailovic

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Contributions

F.C. designed and performed experiments, analyzed data and wrote manuscript. E.R. designed/performed experiments and analyzed data. R.-M.F. performed experiments and analyzed data. T.D. designed experiments and analyzed data. J.Z., Z.W.Z. and J.M., performed experiments. M.S. designed experiments, analyzed data and wrote the manuscript.

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Correspondence to M. Simons.

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Extended data

Extended Data Fig. 1

a-b, western blot analysis of VEGFR2 phosphorylation (pVEGFR2) following stimulation with VEGFA165 (50 ng/ml) or VEGFA121 (50 ng/ml) in Control (Ctr Si) vs. Sdc2-depleted (Sdc2 siRNA) HUVEC. c, VEGFA165 -induced Evans blue leakage in the back skin of WT vs Sdc2iECKO mice (n = 5–6) (representative blots of 3 independent experiments). d, evaluation of baseline permeability in various organs measured as Evans blue dye leakage in Wild type (WT) vs Sdc2-/- mice (n = 3–6). e, f western blot analysis of cell surface protein levels in Control (Ctr) vs. Sdc2-depleted (Sdc2 siRNA) HUVEC (n = 3). Data are presented as mean values + /- SEM (standard error of the mean). In all figure panels, each dot represents a biological independent experiment (n). Statistical analysis was performed by one-way ANOVA with Sidak’s multiple comparison test (panels c, d), and by unpaired t-student test (panel f), (N.S. not significant, * P < 0.05, ** P < 0.01, *** P < 0.001).

Source data

Extended Data Fig. 2

a, confocal image of confluent HUVEC cells in basal conditions showing human DEP1 carrying N-terminal HA-tag (DEP1-HA, red) expression at cell–cell junctions labeled with VE-cadherin (cyan), white arrows, lower panels. Scale bar: 25 μm. b, confocal image of HUVEC cells in basal conditions expressing both human DEP1 carrying N-terminal HA-tag (DEP1-HA, red) and human Sdc2 carrying N-terminal SNAP-tag (SDC2-SNAP, green) proteins. Lower panels show magnification of box in upper panels showing localization of both proteins at the plasma membrane and at the membrane protrusions. Scale bar: 25 μm. c, f, SIM imaging of SDC2/DEP1/Rab5 and SDC2/DEP1/VEGFR2 complexes in HUVECs expressing DEP1-HA and SDC2-SNAP proteins and treated for 20 min with 50 ng/ml VEGFA165. Scale bar: 0.5 μm. d,f, line profile analysis illustrating the distance between DEP1, Sdc2 and Rab5 or DEP1, Sdc2 and VEGFR2 in the same compartment. Plots represent the fluorescent signal in SIM images as a function of position along the line profile in left panel (red dotted line). g, h confocal images of constitutive internalization of DEP1 after incubation for 0 min, 30 min and 60 min in absence of VEGFA in HUVECs control and HUVECs transfected with Sdc2 siRNA. Scale bar: 15 μm. i, confocal image of internalized SDC2–DEP1 complexes in Rab5+ endosomes (white arrows) following constitutive endocytosis in VEGFA-free media. Scale bar: 5 μm. All images are representative images of >3 independent experiments (n). Data are presented as mean values + /- SEM (standard error of the mean). Statistical analysis was performed by two-way ANOVA with Sidak’s multiple comparison test (panels h), (N.S. not significant, * P < 0.05, ** P < 0.01, *** P < 0.001).

Source data

Extended Data Fig. 3

a, position and sequence of DEP1-binding motif in human Sdc2. b, direct ELISA comparing Sdc2 pAb (5 µg/ml) binding to mouse Sdc2 vs. mouse Sdc4. c, bEnd.3 cell proliferation in presence of rabbit IgG (5 µg/ml) or Sdc2 pAb (5 µg/ml) measured with xCELLigence system. d-e, ECs migration measured by in vitro wound-healing assay in bEnd.3 cells in presence of rabbit IgG (5 µg/ml) or Sdc2 pAb (5 µg/ml) (n = 3–4) f-g, TTC staining (at 24 h post stroke) and quantification of stroke infarct in WT vs Sdc2iECKO (n = 5–8). h-i, TTC staining (at 24 h post stroke) in Sdc2-/- mice with or without Sdc2 pAb treatment (administered 1 hour before stroke) (n = 4–9). Data are presented as mean values + /- SEM (standard error of the mean). In all figure panels, each dot represents a biological independent experiment (n). Statistical analysis was performed by one-way ANOVA with Sidak’s multiple comparison test (panels e, i), and by unpaired t-student test (panel g), (N.S. not significant, * P < 0.05, ** P < 0.01, *** P < 0.001).

Source data

Extended Data Fig. 4

MR imaging of IgG and Sdc2 pAb-treated mice: Representative T2 maps from mouse treated with IgG and Sdc2 pAb showing relatively well defined heterogeneous, hyperintense area within right MCA territory with measured T2 values in a range of 0.05–0.09 ms which were higher compared with contralateral normal tissue average 0.03 ms. On the ADC map, in the same region there is hypointense area with low ADC values, range from 0.4–0.8×10–3mm2/s, due to restricted diffusion. In normal appearing contralateral tissue measured ADC values were 0.9–1.1×10-3mm2/s. Compartmentalization analysis (see Material and Methods for details) shows different compartments of ischemic stroke; core (white), penumbra (light green) and edema (dark green).

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Corti, F., Ristori, E., Rivera-Molina, F. et al. Syndecan-2 selectively regulates VEGF-induced vascular permeability. Nat Cardiovasc Res 1, 518–528 (2022). https://doi.org/10.1038/s44161-022-00064-2

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