Adventitial growth factor signalling and vascular remodelling: Potential of perivascular gene transfer from the outside-in

The adventitial segment of the vessel wall has received limited attention compared the endothelium, media and neointima in processes involved in vascular remodelling during atherogenesis, coronary artery bypass graft failure and in response to angioplasty. The adventitia has been regarded as a relatively 'inert' layer providing a supportive connective tissue and extracellular matrix scaffold around vessels for nerves and the vasa vasorum. We and others have recently demonstrated that functional changes in cells within the adventitia contribute to vascular remodelling through the activation and migration of adventitial myofibroblasts, partly under the influence of transforming growth factor-beta1 and platelet derived growth factor-BB. These cytokines stimulate local accumulation of progenitor cells, angiogenesis, matrix deposition and enhanced generation of reactive oxygen species, together contributing to intimal hyperplasia in vascular diseases. This review summarises the evidence that growth factors acting locally in the adventitia can influence vascular function. Furthermore we highlight the therapeutic potential of perivascular gene transfer approaches from the 'outside-in' to antagonise growth factor activity and to modulate expression of vaso- and redox-active genes which act in concert to prevent the progression of vascular diseases in which adventitial cells are activated.