Hypoxia-induced pulmonary vascular remodeling: Contribution of the adventitial fibroblasts

Vascular repair in response to injury or stress (often referred to as remod eling) is a common complication of many cardiovascular abnormalities includ ing pulmonary hypertension, systemic hypertension, atherosclerosis, vein gr aft remodeling and restenosis following balloon dilatation of the coronary artery. It is not surprising that repair and remodeling occurs frequently i n the vasculature in that exposure of blood vessels to either excessive hem odynamic stress (e.g. hypertension), noxious blood borne agents (e.g. ather ogenic lipids), locally released cytokines, or unusual environmental condit ions (e.g. hypoxia), requires readily available mechanisms to counteract th ese adverse stimuli and to preserve structure and function of the vessel wa ll. The responses, which were presumably evolutionarily developed to repair an injured tissue, often escape self-limiting control and can result, in t he case of blood vessels, in lumen narrowing and obstruction to blood flow. Each cell type (i. e, endothelial cells, smooth muscle cells, and fibrobla sts) in the vascular wall plays a specific role in the response to injury. However, while the roles of the endothelial cells and smooth muscle cells ( SMC) in vascular remodeling have been extensively studied, relatively littl e attention has been given to the adventitial fibroblasts. Perhaps this is because the fibroblast is a relatively ill-defined cell which, at least com pared to the SMC, exhibits few specific cellular markers. Importantly thoug h, it has been well demonstrated that fibroblasts possess the capacity to e xpress several functions such as migration, rapid proliferation, synthesis of connective tissue components, contraction and cytokine production in res ponse to activation or stimulation. The myriad of responses exhibited by th e fibroblasts, especially in response to stimulation suggest that these cel ls could play a pivotal role in the repair of injury. This fact has been we ll documented in the setting of wound healing where a hypoxic environment h as been demonstrated to be critical in the cellular responses. As such it i s not surprising that fibroblasts may play an important role in the vascula r response to hypoxia and/or injury. This paper is intended to provide a br ief review of the changes that occur in the adventitial fibroblasts in resp onse to vascular stress (especially hypoxia) and the role the activated fib roblasts might play in hypoxia-mediated pulmonary vascular disease.