Grb2 Is Required for the Development of Neointima in Response to Vascular Injury

OBJECTIVE: Neointima formation occurs in arteries in response to mechanical or chemical injury and is responsible for substantial morbidity. In this work, the role of the intracellular linker protein Grb2 in the pathogenesis of neointima formation was examined. Grb2 is a critical signaling protein that facilitates the activation of the small GTPase ras by receptor tyrosine kinases. METHODS AND RESULTS: Cultured rat aortic smooth muscle cells were treated with an antisense morpholino to Grb2 and these cells showed a reduced proliferative response to platelet-derived growth factor stimulation. Grb2(-/-) mice do not survive embryonic development. Grb2+/- mice appear normal at birth and are fertile but have defective signaling in several tissues. Cultured smooth muscle cells derived from Grb2(+/-) mice grew at a much slower rate than cells derived from Grb2(+/+) mice. Grb2(+/-) and Grb2(+/+) mice were subjected to carotid injury. After 21 days, Grb2(+/+) mice developed robust neointima formation that, in some cases, resulted in an occlusive lesion. In contrast, Grb2(+/-) mice were resistant to the development of neointima CONCLUSIONS: Grb2 is an essential component of the signaling cascade resulting in neointima formation after arterial injury.