Abstract
Angiogenesis is physiologically essential for embryogenesis and development and reinitiated in adult animals during tissue growth and repair. Forming new vessels from the walls of existing vessels occurs as a multistep process coordinated by sprouting, branching, and a new lumenized network formation. However, little is known regarding the molecular mechanisms that form new tubular structures, especially molecules regulating the proper network density of newly formed capillaries. This study conducted microarray analyses in human primary microvascular endothelial cells (HMVECs) plated on Matrigel. The RAPGEF4 gene that encodes exchange proteins directly activated by cAMP 2 (EPAC2) proteins was increased in Matrigel-driven tubulogenesis. Tube formation was suppressed by the overexpression of EPAC2 and enhanced by EPAC2 knockdown in endothelial cells. Endothelial cell morphology was changed to round cell morphology by EPAC2 overexpression, while EPAC2 knockdown showed an elongated cell shape with filopodia-like protrusions. Furthermore, increased EPAC2 inhibited endothelial cell migration, and ablation of EPAC2 inversely enhanced cell mobility. These results suggest that EPAC2 affects the morphology and migration of microvascular endothelial cells and is involved in the termination and proper network formation of vascular tubes.
Highlights
Angiogenesis is physiologically essential for embryogenesis and development and reinitiated in adult animals during tissue growth and repair
This study investigated the global gene expression changes in Matrigel-driven endothelial cell tubulogenesis and demonstrated that exchange proteins directly activated by cAMP 2 (EPAC2) expression was strongly induced in tube-forming microvascular endothelial cells
EPAC2 suppressed endothelial cell migration and changed endothelial cell morphology, suggesting that EPAC2 acts as a negative regulator of an excessively formed network
Summary
Angiogenesis is physiologically essential for embryogenesis and development and reinitiated in adult animals during tissue growth and repair. Increased EPAC2 inhibited endothelial cell migration, and ablation of EPAC2 inversely enhanced cell mobility These results suggest that EPAC2 affects the morphology and migration of microvascular endothelial cells and is involved in the termination and proper network formation of vascular tubes. Angiogenesis, the process by which new vascular networks are formed from preexisting capillaries, is physiologically essential for embryogenesis and development It is reinitiated in adult animals during tissue growth and repair processes, such as wound healing and menstrual cycle[1]. The capillary-like structure of endothelial cells contains a lumen surrounded by cells The advantage of this model is that the molecular dissection of the tube formation can be unveiled because the differentiated cells are compared with undifferentiated, proliferating cells. EPAC2 expressions and functions in endothelial cells remain elusive
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