In this study, we uncovered a novel molecular mechanism governing the mechanical regulation of EC behavior during wound angiogenesis. Thus, WASP family protein-mediated Arp2/3 complex-dependent actin polymerization might regulate vessel elongation during angiogenesis. Functional activities of WASP family proteins including WASP, neuronal-WASP (N-WASP), and WAVE are regulated by Rho family small GTPases, such as Cdc42 and Rac, and Bin-Amphiphysin-Rvs (BAR) domain-containing proteins 19. Consistently, mice deficient in Wave2, a gene encoding a nucleation-promoting factor of the Arp2/3 complex which belongs to the Wiskott–Aldrich syndrome protein (WASP) family proteins, exhibit embryonic lethality due to impaired angiogenesis 18. For instance, Arp2/3 complexes induce the polarized formation of actin-driven junctional-associated intermittent lamellipodia to promote directed EC migration during sprouting angiogenesis 16. Arp2/3 complex-mediated actin polymerization reportedly regulates EC migration and junctional remodeling 15, 16, 17. Previously, we showed that Formin-like 3 regulates the extension of endothelial filopodia to facilitate angiogenic sprouting in zebrafish 14. The actin-related protein 2/3 (Arp2/3) complex and Formin family proteins are key actin nucleators that induce the formation of lamellipodia and filopodia at the leading edge of migrating cells. However, molecular mechanisms by which mechanical forces affect EC behavior to regulate wound angiogenesis remain largely unclear, because methods of analyzing this highly dynamic process in vivo have been lacking.ĭuring angiogenesis, ECs forming the vessel sprouts establish front–rear polarity and migrate by extending actin-based protrusions such as lamellipodia and filopodia at the leading edge. Furthermore, applying external mechanical forces to wounded tissues influences vascular morphogenesis and angiogenesis to promote tissue regeneration 10. The biomechanical force generated by wound contraction also reportedly induces nonangiogenic expansion of pre-existing vessels 13. During wound healing, ECs are stretched and activated by wound contraction to facilitate tissue repair through induction of angiogenesis. Mechanical regulation of angiogenesis is especially important for successful wound healing, a complex and dynamic process by which tissue repairs itself after injury 9, 10, 11, 12. However, the dynamics of EC behavior in angiogenesis and especially its regulation by mechanical forces remain poorly understood. ECs also sense the mechanical properties of the extracellular environment and adapt their behavior accordingly during physiological and pathological angiogenesis 8. Furthermore, blood flow reportedly drives lumen formation by inducing the formation of inverse membrane blebs during angiogenesis 7. It has also been reported that blood flow induces polarized migration of ECs to induce pruning of excessive blood vessels 5, 6. For instance, fluid shear stress is known to control EC sprouting and their elongation direction during angiogenesis 2, 3, 4. Blood flow-driven mechanical forces such as shear stress, hydrostatic pressure, and cyclic stretch play multiple roles in angiogenesis. Not only chemical factors but also mechanical cues act on endothelial cells (ECs) to regulate angiogenesis. Similar content being viewed by othersĪngiogenesis refers to physiological and pathological processes through which new blood vessels form from pre-existing vessels 1. These data indicate that the TOCA family of F-BAR proteins are key actin regulatory proteins required for directed EC migration and sense mechanical cell stretching to regulate wound angiogenesis. In contrast, IP loading expands upstream injured vessels and stretches ECs, preventing leading edge localization of TOCA1 and CIP4 to inhibit directed EC migration and vessel elongation. In downstream injured vessels, F-BAR proteins, TOCA1 and CIP4, localize at leading edge of ECs to promote N-WASP-dependent Arp2/3 complex-mediated actin polymerization and front-rear polarization for vessel elongation. During wound angiogenesis, blood flow-driven IP loading inhibits elongation of injured blood vessels located at sites upstream from blood flow, while downstream injured vessels actively elongate. Herein, we demonstrate a crucial role of blood flow-driven intraluminal pressure (IP) in regulating wound angiogenesis. However, the mechanobiological mechanisms of angiogenesis remain unknown. Angiogenesis is regulated in coordinated fashion by chemical and mechanical cues acting on endothelial cells (ECs).
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