Buchmann Institute for Molecular Life Sciences (BMLS), Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Max-von-Laue-Str. 15, D-60438, Frankfurt am Main, Germany.
Max Planck Institute for Brain Research, Max-von-Laue-Str. 4, 60438, Frankfurt am Main, Germany.
Nat Commun. 2024 Nov 29;15(1):10372. doi: 10.1038/s41467-024-54570-x.
Veins have emerged as the origin of all other endothelial cell subtypes needed to expand vascular networks during developmental and pathological neoangiogenesis. Here, we uncover the role of the angioneurin Fibronectin Leucine Rich Transmembrane protein (FLRT) 2 in central nervous system (CNS) vascular development in the mouse. Early postnatal FLRT2 deletion reveals specific defects in retinal veins, impacting endothelial cell proliferation, sprouting and polarity that result in reduced tip cells at the vascular front. FLRT2 interacts with VE-cadherin and together with the endocytic adaptor protein Numb contribute to the modulation of adherens junction morphology in both retina and cerebral cortex in vivo. Utilizing expansion microscopy, we visualize the altered dynamic distribution of VE-cadherin in tissue of FLRT2 endothelial mutants. Additionally, FLRT2 in cortical vessels regulates the crosstalk between adherens and tight junctions, influencing blood-brain barrier development. Our findings position FLRT2 as a vein-specific regulator of CNS vascular development.
静脉已成为在发育和病理性新血管生成过程中扩展血管网络所需的所有其他内皮细胞亚型的起源。在这里，我们揭示了神经调节蛋白 Fibronectin Leucine Rich Transmembrane protein（FLRT）2 在小鼠中枢神经系统（CNS）血管发育中的作用。新生后早期 FLRT2 缺失揭示了视网膜静脉的特定缺陷，影响内皮细胞的增殖、出芽和极性，导致血管前沿的尖端细胞减少。FLRT2 与 VE-钙黏蛋白相互作用，并与内吞衔接蛋白 Numb 一起，有助于体内视网膜和大脑皮层中黏着连接形态的调节。利用扩展显微镜，我们可以观察到 FLRT2 内皮突变体组织中 VE-钙黏蛋白的改变的动态分布。此外，皮质血管中的 FLRT2 调节着黏着连接和紧密连接之间的串扰，影响血脑屏障的发育。我们的研究结果将 FLRT2 定位为 CNS 血管发育的静脉特异性调节因子。
