Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal.
Institut Curie, Paris Sciences et Lettres Research University, CNRS UMR144, 75005 Paris, France.
Proc Natl Acad Sci U S A. 2021 May 4;118(18). doi: 10.1073/pnas.2023829118.
Sprouting angiogenesis is fundamental for development and contributes to cancer, diabetic retinopathy, and cardiovascular diseases. Sprouting angiogenesis depends on the invasive properties of endothelial tip cells. However, there is very limited knowledge on how tip cells invade into tissues. Here, we show that endothelial tip cells use dactylopodia as the main cellular protrusion for invasion into nonvascular extracellular matrix. We show that dactylopodia and filopodia protrusions are balanced by myosin IIA (NMIIA) and actin-related protein 2/3 (Arp2/3) activity. Endothelial cell-autonomous ablation of NMIIA promotes excessive dactylopodia formation in detriment of filopodia. Conversely, endothelial cell-autonomous ablation of Arp2/3 prevents dactylopodia development and leads to excessive filopodia formation. We further show that NMIIA inhibits Rac1-dependent activation of Arp2/3 by regulating the maturation state of focal adhesions. Our discoveries establish a comprehensive model of how endothelial tip cells regulate its protrusive activity and will pave the way toward strategies to block invasive tip cells during sprouting angiogenesis.
出芽型血管生成对于发育至关重要，并且与癌症、糖尿病性视网膜病变和心血管疾病有关。出芽型血管生成依赖于内皮细胞尖端细胞的侵袭特性。然而，人们对于尖端细胞如何侵入组织知之甚少。在这里，我们表明内皮细胞尖端细胞使用指状伪足作为主要的细胞突起，用于侵入非血管细胞外基质。我们表明，指状伪足和丝状伪足的伸出通过肌球蛋白 IIA（NMIIA）和肌动蛋白相关蛋白 2/3（Arp2/3）的活性来平衡。内皮细胞自主消融 NMIIA 会促进指状伪足的过度形成，从而损害丝状伪足。相反，内皮细胞自主消融 Arp2/3 会阻止指状伪足的发育，并导致丝状伪足过度形成。我们进一步表明，NMIIA 通过调节粘着斑的成熟状态来抑制 Rac1 依赖性的 Arp2/3 激活。我们的发现建立了一个全面的模型，说明了内皮细胞尖端细胞如何调节其伸出活性，并为在出芽型血管生成期间阻止侵袭性尖端细胞的策略铺平了道路。
