Speaker
Description
The lymphatic system is a network of unidirectional vessels that plays an essential role in the control of tissue homeostasis, immune surveillance, and is also involved in metastatic processes [1]. Its function is dynamically regulated by molecular signals — such as vascular endothelial growth factors (VEGFs) — and physical cues. While VEGFs and their associated receptors are known to promote endothelial proliferation [2], their broader roles in tissue organization remain under investigation. Using a lymphatic vessel-on-a-chip platform, we examine how lymphatic endothelial cells (LECs) respond to VEGF-A, VEGF-C, or their combination [3]. We find that co-stimulation synergistically enhances lymphangiogenic sprouting while preserving barrier integrity. Furthermore, co-induces axial polarization of the tissue along the vessel axis, even in the absence of external mechanical stimuli. This polarization requires the activation of the VEGFR2/VEGFR3 heterodimer and is disrupted by inhibition of the Src-dependent mechanotransduction pathway. Further co-stimulation enhances LEC motility and triggers vessel contraction. Finite element modeling suggests that contraction of the tubular geometry creates an intrinsic mechanical anisotropy of the matrix — softer in the circumferential than axial direction. This geometrically-encoded stiffness landscape directs cell migration along the stiffer axis, uncovering a form of durotaxis driven by curvature-induced anisotropy. These results highlight a previously unrecognized mechanism by which biochemical and biophysical cues direct lymphatic tissue polarization, offering new insight into how geometry and mechanosensing shape lymphatic function.
References :
[1] M.A. Swartz, The physiology of the lymphatic system, Adv. Drug Deliv. Rev. 50 (2001) 3–20. https://doi.org/10.1016/S0169-409X(01)00150-8.
[2] Y. Deng, X. Zhang, M. Simons, Molecular Controls of Lymphatic VEGFR3 Signaling, Arterioscler. Thromb. Vasc. Biol. 35 (2015) 421–429. https://doi.org/10.1161/ATVBAHA.114.304881.
[3] J. Edwards, F. Morfoisse, B. Alric, B. Garmy-Susini, Y.T. Matsunaga, A. Bancaud, VEGF-a/C co-stimulation, without shear stress, triggers the polarization of lymphatic microvessels, (2025) 2025.08.13.670220. https://doi.org/10.1101/2025.08.13.670220.