Advertisement

ResearchIn-Press PreviewCell biologyDermatologyVascular biology Open Access | 10.1172/JCI177123

Angiopoietin-like protein 2 mediates vasculopathy driven fibrogenesis in a mouse model of systemic sclerosis

Dyuti Saha,1 Ravi Kiran Annadorai,1 Sujaya Thannimangalath,1 Neha P. Shroff,1 Sunny Kataria,1 Binita Dam,1 Abhik Dutta,1 Akshay Hegde,1 Ankita Hiwale,2 Venkatesh Ravula,2 Shagnik Saha,3 Lekshmi Minikumari Rahulan,4 Neha Nigam,5 Neha Singh,4 Vikas Agarwal,6 Praveen K. Vemula,2 and Colin Jamora7

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Saha, D. in: PubMed | Google Scholar |

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Annadorai, R. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Thannimangalath, S. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Shroff, N. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Kataria, S. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Dam, B. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Dutta, A. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Hegde, A. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Hiwale, A. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Ravula, V. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Saha, S. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Minikumari Rahulan, L. in: PubMed | Google Scholar |

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Nigam, N. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Singh, N. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Agarwal, V. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Vemula, P. in: PubMed | Google Scholar

1Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

2Laboratory of Chemical Biology and Translational Research, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

3Center of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Delhi-NCR, India

4Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

5Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

6Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

7Center for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India

Find articles by Jamora, C. in: PubMed | Google Scholar

Published June 20, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI177123.
Copyright © 2025, Saha et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 20, 2025 - Version history
View PDF
Abstract

Vasculopathy is a common hallmark of various fibrotic disorders including systemic sclerosis (SSc), yet its underlying etiology and contribution to fibrogenesis remain ill-defined. In SSc the vasculopathy typically precedes the onset of fibrosis and we observed that this phenomenon is recapitulated in the Snail transgenic mouse model of SSc. The vascular anomalies manifest as deformed vessels, endothelial cell dysfunction and vascular leakage. Our investigation into the underlying mechanism of this phenotype revealed that angiopoietin-like protein 2 (ANGPTL2), secreted by the Snail transgenic keratinocytes, is a principal driver of fibrotic vasculopathy. In endothelial cells, ANGPTL2 upregulates pro-fibrotic genes, downregulates various junctional proteins, and prompts the acquisition of mesenchymal characteristics. Inhibiting endothelial cell junctional instability and consequently vascular leakage with a synthetic analog of the microbial metabolite Urolithin A (UAS03) effectively mitigated the vasculopathy and inhibited fibrogenesis. Thus, ANGPTL2 emerges as a promising early biomarker of the disease and inhibiting the vasculopathy inducing effects of this protein with agents such as UAS03 presents an appealing therapeutic avenue to reduce disease severity. These insights hold the potential to revolutionize the approach to the treatment of fibrotic diseases by targeting the vascular defects.

Graphical Abstract
graphical abstract
Supplemental material

View

View Supplemental table 1

View Supplemental table 2

Version history
  • Version 1 (June 20, 2025): In-Press Preview
Advertisement
Advertisement