Endothelial cell invasion is controlled by dactylopodia
Ana M. Figueiredo, Pedro Barbacena, Ana Martins Russo, Silvia Vaccaro, Daniela Ramalho, Andreia Pena, Aida P. Lima, Rita R. Ferreira, Marta Fidalgo, Fatima El-Marjou, Yulia Carvalho, Francisca F. Vasconcelos, Ana‐Maria Lennon‐Duménil, Danijela Matic Vignjevic, Cláudio A. Franco
Abstract
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.