Abstract
Angiopoietin-1 (Ang-1) is an important proangiogenic factor also involved in the maintenance of endothelial-barrier integrity. The small GTPase Rap1 is involved in the regulation of adherens junctions through VE-cadherin-mediated adhesion, and in endothelial permeability. While many studies established that Rap1 activation is critical for endothelial cell–cell adhesions, its roles in the antipermeability effects of Ang-1 are ill-defined. Thus, we determined the contribution of Rap1 to Ang-1-stimulated angiogenic effects on endothelial cells (ECs). We found that Rap1 is activated following Ang-1 stimulation and is required for the antipermeability effects of Ang-1 on EC monolayers. Our results also revealed that Rap1 is necessary for EC sprouting stimulated by Ang-1 but had no significant effect on Ang-1-induced EC migration and adhesion. In contrast, downregulation of VE-cadherin markedly increased the adhesiveness of ECs to the substratum, which resulted in inhibition of Ang-1-stimulated migration. These results revealed that Rap1 is central to the effects of Ang-1 at intercellular junctions of ECs, whereas VE-cadherin is also involved in the adhesion of ECs to the extracellular matrix.
Highlights
Angiogenesis is the process by which new blood vessels emerge from existing ones
In siVE-cadherin-transfected cells, a marked increase in focal adhesions (FAs) numbers and a decrease in the size of FAs was observed basally. These effects were enhanced in Ang-1-stimulated Bovine aortic endothelial cells (BAECs) (Figure 5C–E). These results suggest that Rap1 is not involved in endothelial cells (ECs) migration and adhesion stimulated by Ang-1, while VE-cadherin depletion results in a marked increase of adhesion, which prevents EC migration stimulated by Ang-1
Graphs are representative of three independent experiments each yielding similar results; * p < 0.05. Various angiogenic factors such as thrombin, sphingosine 1-phosphate, and vascular endothelial growth factor (VEGF) rely on Rap1 activity to regulate endothelial permeability, migration, tube formation, integrin-mediated adhesion, and EC polarity [21,22,23,24,25,26,27]
Summary
Angiogenesis is the process by which new blood vessels emerge from existing ones. It is involved in many biological processes, including embryonic development, reproduction, and wound repair [1,2].an imbalance in the angiogenic process participates in the establishment of many malignant diseases such as cancer, and inflammatory, ischaemic, and immune disorders. Angiogenesis is the process by which new blood vessels emerge from existing ones. It is involved in many biological processes, including embryonic development, reproduction, and wound repair [1,2]. An imbalance in the angiogenic process participates in the establishment of many malignant diseases such as cancer, and inflammatory, ischaemic, and immune disorders. Dynamic regulation of the endothelial barrier is crucial for angiogenesis during development to promote the maturation of blood vessels. This barrier is preserved by adherens junctions (AJs) and tight junctions (TJs), both of which are linked to the actin cytoskeleton, and it maintains tissue integrity
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