Figure 3.

Factors driving the evolution of pulmonary vascular obstructive disease. Endothelial dysfunction reduces release of prostacyclin and nitric oxide (NO), causes adherence of activated platelets and leucocytes, enhanced release of thromboxane and endothelin, and loss of barrier function with leakage of serum factor into the subendothelium. This last action is thought to heighten activity of metalloproteinases (MMPs), including the proteolytic enzyme endogenous vascular elastase (EVE)¹⁴,²¹ released from smooth muscle cells, to help induce structural remodelling, cause smooth muscle cell activation, disruption of the internal elastic lamina, and facilitate smooth muscle cell migration. MMPs also activate growth factors normally sequestered in the matrix in an inactive form. Increased tenascin expression is associated with cell proliferation, its downregulation with apoptosis. Tenascin amplifies the proliferative response to epidermal growth factor and fibroblast growth factor (FGF)-2 in vitro. Expression of fibronectin is widespread and this glycoprotein can facilitate smooth muscle migration. The innermost smooth muscle cells cease to express many smooth muscle specific contractile and cytoskeletal proteins before migrating through gaps in the internal elastic lamina. Changes in phenotype are widespread.