NIH grant: Endothelial fate switches and function via matrix control of adherens junctions (1R01HL183648-01)

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NIH grant 1R01HL183648-01: Endothelial fate switches and function via matrix control of adherens junctions
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: Brendon M Baker. Award: $724200.
Start: 2026-07-10T00:00:00.
PROJECT SUMMARY
Fibrogenesis is essential for wound healing but, when dysregulated, contributes to fatal diseases like solid
cancers, pulmonary fibrosis, and cirrhosis. All tissues or organs that are susceptible to fibrosis contain not only
resident fibroblasts but also microvasculature critical to fluidic transport of nutrients and waste exchange.
Although the cellular precursors and signaling that engender myofibroblasts (MF), mediators of wound healing
that excessively secrete extracellular matrix (ECM), have been a major target to date, the current lack of effective
anti-fibrotic therapies suggests the critical involvement of other cellular players. Endothelial-mesenchymal
transition (EndMT) is believed to portend the expansion of functional neovessels to support wound healing, but
how this process can be dysregulated by fibrosis-driven matrix remodeling has not been established. In fact,
while EndMT has previously been implicated as a precursor to endothelial cell (EC) differentiation into MFs,
alternative mechanisms through which EndMT contributes to fibrosis have not been considered. Here, motivated
by strong preliminary data acquired by the investigative team, we demonstrate, using mouse models and in an
in vitro human microphysiological system (MPS) of arteriole/venule-scale microvessels embedded within a
tunable stromal mimetic matrix, that fibrotic physical cues activate ECs, drive EndMT, and promote aberrant
single EC (sEC) invasion into the matrix. sECs remain adherent to fibrotic matrix and may reinforce fibrogenesis
through signaling interactions with other stromal cells. Critically, we identify that the formation of sECs is gated
by the destabilization of EC adherens junction (AJs) upon EC adhesion to fibrous matrix. We find that quiescent
EC microvessels in healthy matrix do not respond to TGFβ, but adhesion to fibrotic matrix destabilizes AJs to
promote TGFβ-mediated signaling. Further, using unbiased proteomics, we have uncovered a novel interaction
between the AJ adhesion receptor CDH5 (VE-cadherin) and TGFβR2 that is controlled by EC-ECM interactions.
This project leverages two highly complementary labs, next generation MPS culture models, genetically
engineered mouse models, and mechanistic studies to dissect EC decision-making and function in response to
fibrotic cues, testing the central hypothesis that fibrotic ECM drives EC fate switching to reinforce fibrogenic
signals underlying tissue fibrosis. In Aim 1, we will identify what fibrogenic physical and soluble signals are
associated with sECs and test whether these signals allow sECs to modulate the states of other stromal cells to
promote fibrogenesis. In Aim 2, we deeply investigate the mechanism by which EC adhesion to fibrous matrix
promotes sEC formation and test whether a critical CDH5-TGFβR2 association is modulated by fibrotic ECM to
potentiate EC TGFβ signaling. Completion of these studies will define: new mechanisms by which ECM control
EC fate, new functional contributions of ECs to fibrogenesis, and a previously-unappreciated mechanism
governing EC fate and function operating at EC AJs. These insights offer the potential for new anti-fibrotic
therapeutics and associated mechanism of action for future investigation in pre-clinical studies.

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