Figure 8. Hypothetical synopsis of the development of PH in experimental PF.

Transient overexpression of active TGF-β1 in rodent lung induces PF with myofibroblast accumulation and deposition of ECM. VEGF and VEGF signaling are decreased early on during fibrogenesis by direct actions of TGF-β1 as a result of tissue damage (e.g., epithelial apoptosis) or by secondary mediators such as PEDF. The consequence of decreased VEGF is reduced eNOS expression, with the result being apoptosis of ECs and vascular rarefaction. In addition, other secondary mediators (e.g., angiotensin II, endothelin-1) are released as an effect of EC apoptosis (earlier) and fibrogenesis (later) and induce remodeling of PA walls together with TGF-β. All these processes, reduced vascular density, and mediator-related PA remodeling finally culminate in PH, which will augment the remodeling process of PA in the form of a vicious circle. Note the central importance of EC apoptosis for both reduced vascular density and PA muscularization in this concept.