Perivascular cells function as key mediators of mechanical and structural changes in vascular capillaries
A hallmark of chronic and inflammatory diseases is the formation of a fibrotic and stiff extracellular matrix (ECM), typically associated with abnormal, leaky microvascular capillaries. Mechanisms explaining how the microvasculature responds to ECM alterations remain unknown. Here, we used a microphysiological model of capillaries on a chip mimicking the characteristics of healthy or fibrotic collagen to test the hypothesis that perivascular cells mediate the response of vascular capillaries to mechanical and structural changes in the human ECM. Capillaries engineered in altered fibrotic collagen had abnormal migration of perivascular cells, reduced pericyte differentiation, increased leakage, and higher regulation of inflammatory/remodeling genes, all regulated via <i>NOTCH3</i>, a known mediator of endothelial-perivascular cell communication. Capillaries engineered either with endothelial cells alone or with perivascular cells silenced for <i>NOTCH3</i> expression showed a minimal response to ECM alterations. These findings reveal a previously unknown mechanism of vascular response to changes in the ECM in health and disease.
Authors
- Ramesh Subbiah (ORCID: https://orcid.org/0000-0003-0044-9740)
- Cristiane Miranda França (ORCID: https://orcid.org/0000-0002-9285-4622)
- Aaron R. Doe (ORCID: https://orcid.org/0000-0001-6650-2001)
- Amin Mansoorifar (ORCID: https://orcid.org/0000-0003-0539-4793)
- Avathamsa Athirasala (ORCID: https://orcid.org/0000-0002-2908-9403)
- Maurício Gonçalves da Costa Sousa (ORCID: https://orcid.org/0000-0001-6009-035X)
- Keith Beadle (ORCID: https://orcid.org/0000-0002-5695-6461)
- Alice Corrêa Silva‐Sousa (ORCID: https://orcid.org/0000-0002-9931-0935)
- Kenneth M. Yamada (ORCID: https://orcid.org/0000-0003-1512-6805)
- Jennifer Bays (ORCID: https://orcid.org/0000-0003-0218-2680)
- May Anny Alves Fraga (ORCID: https://orcid.org/0000-0002-9323-0862)
- Emilios K. Dimitriadis (ORCID: https://orcid.org/0000-0002-2089-5361)
- Maria Elisa Quezado Lima Verde (ORCID: https://orcid.org/0000-0002-8563-6299)
- Anthony Tahayeri (ORCID: https://orcid.org/0000-0001-6590-6928)
- Marina Uroz (ORCID: https://orcid.org/0000-0003-4124-8048)
- Rahul Madathiparambil Visalakshan (ORCID: https://orcid.org/0000-0001-8698-1783)
- Christopher S. Chen (ORCID: https://orcid.org/0000-0003-2445-8449)
- McKenna Finley (ORCID: https://orcid.org/0009-0005-1632-3212)
- Luiz E. Bertassoni
Institutions
- Boston University (US)
- National Institutes of Health (US)
- Harvard University (US)
- Oregon Health & Science University (US)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Cancer Institute (WIA) (IN)
- National Institute of Biomedical Imaging and Bioengineering (US)
- National Institute of Dental and Craniofacial Research (US)
- Methodist University of Piracicaba (BR)
- University of Portland (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-01-10
- DOI
- https://doi.org/10.1126/sciadv.adp3789
- Citations
- 20
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 19.86