Cdh5/VE-cadherin Promotes Endothelial Cell Interface Elongation via Cortical Actin Polymerization during Angiogenic Sprouting

Abstract

Organ morphogenesis requires the coordination of cell behaviors. Here, we have analyzed dynamic endothelial cell behaviors underlying sprouting angiogenesis in vivo. Two different mechanisms contribute to sprout outgrowth: tip cells show strong migratory behavior, whereas extension of the stalk is dependent upon cell elongation. To investigate the function of Cdh5 in sprout outgrowth, we generated null mutations in the zebrafish cdh5 gene, and we found that junctional remodeling and cell elongation are impaired in mutant embryos. The defects are associated with a disorganization of the actin cytoskeleton and cannot be rescued by expression of a truncated version of Cdh5. Finally, the defects in junctional remodeling can be phenocopied by pharmacological inhibition of actin polymerization, but not by inhibiting actin-myosin contractility. Taken together, our results support a model in which Cdh5 organizes junctional and cortical actin cytoskeletons, as well as provides structural support for polymerizing F-actin cables during endothelial cell elongation.

Endothelial basement membrane laminin 511 is essential for shear stress response

“…Our work demonstrated that the presence of laminin α5 in endothelial basement membrane correlates with increased endothelial cell cortical stiffness in vivo and in vitro , which suggests changes in cortical actin arrangement may also mechanically affect junctional proteins (Engl et al , 2014; Sauteur et al , 2014). Although it is very difficult to prove, the absence of a single molecule such as laminin 511 from the basement membrane is unlikely to affect the overall stiffness of the matrix, plus the stiffness of the glass on which isolated laminins were plated in the AFM experiments is likely to override any laminin‐specific effects.…”

Cell behaviors and dynamics during angiogenesis

“…cell elongation. This EC elongation is reflected and driven by the remodeling of EC junctions and requires the adhesion molecule Cdh5/VE-cadherin as well as F-actin polymerization (Sauteur et al, 2014). Cell shape changes based on junctional remodeling are not only associated with EC elongation during sprout outgrowth, but also with EC rearrangements observed during anastomosis and pruning; cell rearrangements thus not only tightly accompany the angiogenesis process, they represent a major aspect all three steps of angiogenesis.…”

“…Interestingly, the sprout does not only extend by cell proliferation; recent studies have revealed that cell elongation and cell rearrangements are important components of stalk elongation (Sauteur et al, 2014). EC elongation is driven by the transition of junctional contacts from a roundish to an eliptic form; this change requires the adhesion molecule VE-cadherin, as well as actin polymerization.…”

Distinct and redundant functions of Esama and VE-cadherin during vascular morphogenesis

“…Tip cells in the nascent sprout migrate extensively and form numerous filopodia, whereas the following stalk cells undergo extensive cell and junctional elongation (Gerhardt et al, 2003;Phng et al, 2013;Sauteur et al, 2014). This characteristic stalk cell behavior extends the sprouts in the dorsal direction and leads to the formation of a multicellular tube.…”