**4. Summary**

alveolar development improves, PH is reversed barring associated co-morbidities, which can have a negative influence. In the latter cases (PH associated with CHD), closure of the defect in a timely fashion is effective. However, in some instances PH may progress despite the correction of the underlying defect. Most clinical and experimental studies suggest that the status of EC may determine the reversibility or irreversibility. In MCT-induced PH, progres‐ sive disruption of endothelial caveolin-1 is accompanied by the activation of proliferative and anti-apoptotic pathways. At 2 wks post-MCT, PH is accompanied by the loss of cytosolic proteins indicating further EC damage. Loss of vWF which is stored in Weibel Palade bodies within the EC occurs at 4 wks post-MCT, indicative of extensive EC damage or loss. This is accompanied by enhanced expression of caveolin-1 in SMC and increased expression and activity of MMP2. These changes can lead to further cell proliferation, cell migration and possible neointima formation. Interestingly, EC apoptosis is reported to be followed by exuberant apoptotic resistant EC [Huang 2010, Huang 2012, Sakao 2005]. This view is sup‐ ported by a recent case report showing loss of endothelial caveolin-1 and vWF; and associated enhanced expression of caveolin-1 in SMC, followed by neointima formation [Mathew 2011c].

Loss of miR-21, which is abundant in EC, occurs in patients with IPAH and HPAH, and in MCT-induced PH but not in hypoxia-induced PH [Caruso 2010, Drake 2011]. This is a significant observation, because unlike MCT, hypoxia-induced PH does not lead to endothelial disruption [Mathew 2011b] and PH reverses when hypoxia is discontinued [Sluiter 2012]. These observed differences in miR-21 expression, therefore, are very likely dependent on the underlying status of EC. These observations support the view that the EC integrity may determine the eventual outcome of the disease as shown in the proposed model (Figure 1).

**Figure 1.** This figure depicts proposed pathways in PH. Injury in patients with or without susceptibility evokes an in‐ flammatory response resulting in disruption or perturbation of endothelial cell membrane leading to the activation of proliferative and antiapoptotic pathways and PH. The status of endothelial cell membrane may determine the reversi‐

bility or irreversibility of PH.

62 Pulmonary Hypertension

PH is the result of an imbalance between vasoconstriction and vasodilatation, cell proliferation and apoptosis, and between pro-angiogenesis and anti-angiogenesis. Intricate and delicate intermeshing of a large number of signaling molecules in pulmonary vasculature cooperate to preserve the balance between the opposing signaling and activities, thus, maintain vascular health. Loss or increased expression of a molecule secondary to an injury can derail the delicate network of signaling pathways resulting in deregulated inflammatory response, cell prolifer‐ ation, cell migration and angiogenesis leading to the initiation and progression of PH. Some of these changes occur before PH becomes clinically manifest, thus, impacting the response to therapy and survival. Genetics, epigenetics, severity of injury and the associated inflammatory response further influence the outcome.
