Background: Activin receptor-like kinase 1 (ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasia (HHT), a devastating disorder that leads to arteriovenous malformations (AVMs). Here we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles. Methods: Using Cre lines that recombine in different subsets of arterial, capillary-venous or endothelial tip cells, we showed that capillary-venous Alk1 deletion was sufficient to induce AVM formation in the postnatal retina. Results: ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro . Mechanistically, ALK1 deficient cells exhibited increased integrin signaling interaction with VEGFR2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacological inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in Alk1 deficient mice. Conclusions: Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of AVM formation in HHT disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in HHT patients.

Plasmon coupling is the fundamental principle by which the optical resonances in nanoparticle assemblies are tuned. Interactions of plasmons among nanoparticles in close proximity create plasmon coupling modes whose energies are sensitive to the nanogap parameters. Whereas many studies have focused on the gap distances, we herein probe the effect of gap morphology on plasmon coupling. Dimers that are prepared by adsorbing perfectly round ultrauniform Au nanospheres (AuNSs) onto the faces, edges, and vertices of Au nanocubes (AuNCs) present distinctly different nanogap morphologies. Dark-field single-particle scattering spectroscopy reveals that the longitudinal plasmon coupling mode shifts to lower energies as the AuNS forms a nanogap with parts of the AuNC with higher curvature. Simulation spectra are also consistent with this observation. Our calculations indicate that the much larger charge density at the vertex or edge of a AuNC lowers the plasmon coupling energy through the contribution of the Coulomb interaction when the AuNC combines with the AuNS. In comparison, the plasmon energies or anisotropic polarizability along the face, edge, and vertex directions of a AuNC differ only slightly and thus do not cause a shift in the plasmon coupling mode.

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AMIGO2 is a novel scaffold protein that regulates PDK1 membrane localization and Akt activation in endothelial cells, and inhibition of the interaction between PDK1–AMIGO2 results in impaired neovascularization, pathological angiogenesis, and tumor angiogenesis.

Hot electron chemistry is of paramount significance because of its applicability to photocatalytic reactions, solar energy conversion, and waste decomposition. The nonradiative decay of excited plasmons in gold nanoparticles (AuNPs) generates highly energetic nonthermal electrons and holes that can induce chemical reactions when transferred to nearby molecules. In this study, we explore the relationship between AuNP size (26−133 nm) and the plasmoninduced reaction yield. To isolate the size from other structural parameters, we prepare perfectly round gold nanospheres (AuNSs) with narrow size distributions. The use of a nanoparticle-on-mirror configuration, in which the reactant molecules (4-mercaptobenzoic acid) are positioned in nanogaps between the AuNSs and a Au film, promotes the generation of hot carriers and allows the highly sensitive detection of the reaction products (benzenethiol) using surface-enhanced Raman spectroscopy. We show that the reaction yield increases as the AuNS size increases up to 94 nm and then decreases for larger AuNSs. This peculiar Λ-shaped size-dependent reactivity can be explained by considering both the plasmonic absorption efficiency of AuNSs and the decay rate of plasmons via electron-surface scattering. The product of the calculated absorption cross section and the inverse of the AuNS size reproduces our experimental results remarkably well. These findings will contribute to the design of highly efficient plasmonic photocatalysts and photovoltaic devices.