Substrate Matters

Abstract

See related article, pages 570–580 The integrin family of transmembrane receptors is composed of heterodimers of different α and β subunits that direct cellular adhesion to extracellular matrix (ECM) components such as collagens, laminins, fibronectin, and vitronectin. Certain members of the integrin family, such as α2β1, α5β1, αvβ3, and αvβ5 integrins, are specifically upregulated in endothelial cells during angiogenesis, eg, during vascular remodeling and growth associated with inflammation, wound healing, ischemic injury, or tumor growth.1 Functional inhibition of these integrins, via blocking antibodies or cyclic peptide antagonists, has been found to reduce angiogenic responses to growth factors, ischemia, and tumors.2 Thus, in addition to their involvement in steady-state maintenance of blood vessel integrity, integrins seem to play an essential role in the carry-out of angiogenic programs in activated endothelial cells. The integrin signaling is bidirectional and encompasses both outside-in signals, eg, activation of second messenger pathways in response to changes in ECM composition, and inside-out signals, eg, changes in cellular adhesion and motility in response to growth factor stimulation.3 In addition, there is a degree of interdependence between the cellular circuits processing ECM-derived signals and soluble growth factor–derived signals. For instance, growth factor–induced responses are modulated by cellular adhesion, and integrin-mediated outside-in signals, dependent on the specific type of integrin molecule(s) engaged by the ECM, seem to directly influence growth factor receptor signaling pathways.4,5 The reciprocal communication between integrins and growth factor receptors most likely acts to integrate and coordinate cellular activity in response to different types of stimuli. However, the molecular mechanisms involved and the direct functional consequences of the cross-talks between integrins and growth factor receptors have only recently begun to unravel. Interestingly, several growth factor receptors, including …