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bioRxiv · 10.1101/2025.06.30.662394

Latrophilin-2 Orchestrates Endothelial Flow-Mediated Smad1/5 Activation via Endoglin and Shank3

Tanaka, K.·Chanduri, M. V.·Chen, M.·Prendergast, A.·Mani, A.·Schwartz, M. A.
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Abstract

Fluid shear stress (FSS) from blood flow critically determines vascular morphology and function. FSS activates the Smad1/5 pathway maximally at physiological FSS through the BMP9/10 receptors Alk1 and Endoglin to promote vascular stability. We now report that the adhesion G protein-coupled receptor Latrophilin-2 (Lphn2), which mediates flow activation of the canonical junctional complex, is required for flow-mediated Smad1/5 activation in endothelial cells. Lphn2 physically associates with Endoglin and is required for Smad1/5 activation by FSS but not soluble BMP9. This regulation is independent of G-proteins but requires Lphn2s C-terminal PDZ binding motif. Endothelial-specific Lphn2 knockout reduces Smad1/5 activation in mice. In zebrafish embryos, loss of flow or Lphn2 knockout similarly reduced endothelial Smad1/5 activation, with no additive effect, indicating that Lphn2 mediates flow-induced activation in vivo. APEX2 proximity labeling revealed that the PDZ domain-containing scaffold protein Shank3 associated with Lphn2 under flow. Shank3 knockdown blocked flow-induced Smad1/5 activation in vitro and Shank3 global knockout mice exhibited reduced endothelial nuclear Smad1/5 and increased susceptibility to arteriovenous malformations. Lphn2 thus mediates flow-induced Smad1/5 activation and vessel stabilization through the scaffold protein Shank3, independently of G proteins. Together with the accompanying paper on Notch1, we conclude that Lphn2 confers FSS sensitivity to three of the major FSS pathways via distinct mechanisms.

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Tanaka, K., Chanduri, M. V., Chen, M., Prendergast, A., Mani, A., Schwartz, M. A.. 2025-07-03. Latrophilin-2 Orchestrates Endothelial Flow-Mediated Smad1/5 Activation via Endoglin and Shank3. https://doi.org/10.1101/2025.06.30.662394

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