TY - JOUR
T1 - Endothelial cell invasion is controlled by dactylopodia
AU - Figueiredo, Ana Martins
AU - Barbacena, Pedro
AU - Russo, Ana
AU - Vaccaro, Silvia
AU - Ramalho, Daniela
AU - Pena, Andreia
AU - Lima, Aida Pires
AU - Ferreira, Rita Rua
AU - Fidalgo, Marta Alves
AU - El-Marjou, Fatima
AU - Carvalho, Yulia
AU - Vasconcelos, Francisca Ferreira
AU - Lennon-Duménil, Ana Maria
AU - Vignjevic, Danijela Matic
AU - Franco, Cláudio Areias
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Clare M. Waterman, Robert Fischer, Robert Adelstein, and Xuefei Ma (National Heart, Lung, and Blood Institute) for discussion and technical support and João Barata, Edgar Gomes (Instituto de Medicina Molecular), and Michael Potente (Max Planck Institute for Heart and Lung Research) for critical review of the manuscript. We thank all members of the Vascular Morphogenesis Laboratory for helpful discussions and critical reading of the manuscript. C.A.F. was supported by a European Research Council starting grant (679368), the European Union H2020-TWINN-2015—Twinning (692322), the Fundação para a Ciência e a Tecnologia funding (grants IF/00412/2012, EXPL/BEX-BCM/2258/2013, PTDC/MED-PAT/31639/2017, and PTDC/BIA-CEL/32180/2017 and fellowships CEECIND/04251/2017 and CEE-CIND/02589/2018), and a grant from the Fondation Leducq (17CVD03).
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/5/4
Y1 - 2021/5/4
N2 - 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.
AB - 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.
KW - Actin
KW - Angiogenesis
KW - Endothelial cells
KW - Invasion
KW - Myosin
UR - http://www.scopus.com/inward/record.url?scp=85105612007&partnerID=8YFLogxK
U2 - 10.1073/pnas.2023829118
DO - 10.1073/pnas.2023829118
M3 - Article
C2 - 33903241
AN - SCOPUS:85105612007
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 18
M1 - 2023829118
ER -
