Abstract
Collagen I provokes endothelial cells to assume a spindle-shaped morphology and to align into solid cord-like assemblies. These cords closely imitate the solid pre-capillary cords of embryonic angiogenesis, raising interesting questions about underlying mechanisms. Studies described here identify a critical mechanism beginning with collagen I ligation of integrins alpha(1)beta(1) and alpha(2)beta(1), followed by suppression of cyclic AMP and cyclic AMP (cAMP)-dependent protein kinase A, and marked induction of actin polymerization to form prominent stress fibers. In contrast to collagen I, laminin-1 neither suppressed cAMP nor protein kinase A activity nor induced actin polymerization or changes in cell shape. Moreover, fibroblasts did not respond to collagen I with changes in cAMP, actin polymerization, or cell shape, thus indicating that collagen signaling, as observed in endothelial cells, does not extend to all cell types. Pharmacological elevation of cAMP blocked collagen-induced actin polymerization and formation of cords by endothelial cells; conversely, pharmacological suppression of either cAMP or protein kinase A induced actin polymerization. Collectively, these studies identify a previously unrecognized and critical mechanism, involving suppression of cAMP-dependent protein kinase A and induction of actin polymerization, through which collagen I drives endothelial cell organization into multicellular pre-capillary cords.
Highlights
During angiogenesis, proliferating endothelial cells (ECs)1 organize to form new three-dimensional capillary networks
Latrunculin A blocked collagen-induced actin polymerization in microvascular ECs (MVECs), and it blocked collagen-induced changes in cell shape (Fig. 3B). These experiments establish that actin polymerization is critical to the mechanism by which collagen I initiates MVEC alignment into cords
Collagen I provokes MVECs in vitro to assume a spindleshaped morphology and to align into solid cord-like assemblies. These cords, which are organized in polygonal arrays, closely imitate the polygonal patterns of embryonic pre-capillary cords that precede the formation of mature blood vessels with lumens in vivo [1, 2, 4, 29]
Summary
During angiogenesis, proliferating endothelial cells (ECs)1 organize to form new three-dimensional capillary networks. Studies described here identify a critical mechanism beginning with collagen I ligation of integrins ␣11 and ␣21, followed by suppression of cyclic AMP and cyclic AMP (cAMP)-dependent protein kinase A, and marked induction of actin polymerization to form prominent stress fibers. In contrast to collagen I, laminin-1 neither suppressed cAMP nor protein kinase A activity nor induced actin polymerization or changes in cell shape.
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