10. PROFIL DU GROUPE DE LOCUTEURS
10.3. Analyse épilinguistique du discours des locuteurs
Under normal conditions, the structure of the pulmonary arterial wall is maintained by a fine balance between proliferation and apoptosis of PASMCs, PAECs and fibroblasts. In PAH this balance is disrupted, and PAH is characterised by intimal thickening and muscularisation of the distal, previously non-muscular pulmonary arteries, resulting in a narrowed lumen and subsequent impairment of blood flow. This process is termed pulmonary vascular remodelling and is considered the hallmark in PAH (Tuder et al. 2009). Pulmonary vascular remodelling involves all three cell types in the vascular wall and arises from an increase in proliferation combined with suppression of apoptosis (Mandegar et.al. 2004).
1.3.2.1 The Role of Smooth Muscle Cells in Pulmonary Vascular Remodelling
Smooth muscle cells underlie the pulmonary vascular remodelling process.
Smooth muscle hypertrophy and hyperplasia play an integral role in intimal and medial thickening which is widely observed in mild/early-stage PAH (Figure 1-9).
In addition, smooth muscle cells and fibroblasts begin to produce increased matrix proteins, including collagen and elastin, within the media and adventitia contributing to medial thickness (Jeffery & Morrell 2002). During PAH, changes in the phenotype of PASMCs are also described, for example, PASMCs taken from PAH patients exhibit a more proliferative phenotype (Eddahibi et al. 2001). An increased migratory smooth muscle cell phenotype is also described. One common feature to PAH is the distal progression of smooth muscle cells into the normally non-muscular small peripheral pulmonary arteries resulting in muscularisation of the terminal portion of the pulmonary artery (MacLean et.al.
2000). Migration from the media to the subendothelial layer results in a layer of cells situated between the endothelium and the internal elastic lamina, termed the neointima (Yi et al. 2000). In the neointima, the smooth muscle cell phenotype alters from contractile to synthetic and secretes excessive extracellular matrix proteins contributing significantly to increased vascular resistance (Olschewski et al. 2001).
1.3.2.2 The Role of Endothelial Cells in Pulmonary Vascular Remodelling In severe and end-stage PAH, another important form of vascular remodelling is observed involving disorganised proliferation and apoptosis of endothelial cells leading to formation of ‘plexiform lesions’ (Cool et al. 1997; Tuder et al. 1994).
Plexiform lesions (Figure 1-9) are typically seen arising from smaller resistance arteries (200-400µm) distal to the bifurcation site and are described as complex, glomeruloid-like vascular structures (Cool et al. 2005; Sakao et al. 2009). They appear to have a complex inflammatory microenvironment distinct from remodeled arteries in PAH lungs. The continuous proliferation and sprouting of vascular channels is associated with up-regulation of hypoxia and shear stress-induced angiogenic mediators, such as HIF1a, VEGF-α and TGF-β1 (Jonigk et al.
2011). In addition, loss of tumour suppressor gene peroxisome proliferator-activated receptor-γ (PPAR-γ), is reported in plexiform lesions of PAH patients (Ameshima et al. 2003). PPAR-γ is antiproliferative and anti-inflammatory (Jiang et al. 1998) and has previously been shown to mediate an important protective role in experimental PAH (Hansmann et al. 2008). Decreased production of vasodilators (Tuder et.al. 1999) and increased production of vasoconstrictors (Giaid et al. 1993) is also described in these plexiform lesions.
Regardless of the histopathologic subtype involved, pulmonary vascular remodelling always results in obstruction of the lumen and the impairment of blood flow leading to increased vascular resistance.
Importantly experimental animal models of PAH fail to recapitulate the severe vascular phenotype in PAH with neointimal formation and plexiform lesions. The role plexiform lesions play in the pathogenesis of human PAH is therefore controversial. However, the discovery of novel animal models of PAH appears to show endothelial cell proliferation, luminal obliteration and severe PAH as a result of plexiform lesions and neointimal changes. For example, S100A4/Mts1 protein over-expressing mice (Dempsie et al. 2011; Greenway et al. 2004), schistosomiasis murine model (Crosby et al. 2010) and administration of VEGF receptor antagonist Sugen 5416 + hypoxia rat model (Abe et al. 2010). Since these lesions appear to have morphology similar to human plexiform lesions, a better understanding of human pathology is achievable.
57 1.3.2.3 Downstream Signalling Involved in Vascular Remodelling
Akt, or protein kinase B, is a serine/threonine-specific protein kinase that plays a critical role in cell apoptosis, proliferation and migration. In addition, Akt signalling is a critical mediator of cardiac hypertrophy, survival and stress. It is recognised that the survival signal mediated by various growth factors and cytokines involves phosphatidylinositol 3’-kinase (PI3K)/Akt signal transduction pathway. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) can induce PI3K activity in aortic endothelial cells (Guo et al.
1995; Xia et al. 1996) and PASMCs (Goncharova et al. 2002). Recent evidence has also highlighted an important role of increased thrombin-induced Akt phosphorylation in PASMCs in IPAH and CTEPH resulting in increased proliferation and leading to medial hypertrophy and vascular remodelling (Ogawa et al. 2013).
Interestingly, Akt phosphorylation is also regulated by estrogen. Reduced Akt signal transduction by estrogen reverses remodeling secondary to PH (Nadadur et al. 2012) and significantly reduces Akt signalling during right heart failure in PH (Nadadur et al. 2012).
The mitogen-activated protein kinase (MAPK)/ extracellular signal-related kinase (ERK) pathway is also crucially involved in vascular remodeling and cardiac hypertrophy. MAPK cascades are highly conserved signal transduction pathways and are believed to regulate cell and myocyte growth in response to developmental signals or physiologic and pathologic stimuli (Meng et al. 2011).
Previous studies have demonstrated that ERK and p38 MAPK expression are increased in cardiac hypertrophy (Altamirano et al. 2009; Streicher et al. 2010).
In the pulmonary vasculature, MAPK/ERK also plays a central role in smooth muscle cells in response to mechanical, hypoxic and growth-factor induced stimuli, in particular promoting PASMC growth (Mandegar et al. 2004). Estrogen is also involved in regulation of ERK and leads to a decline in ERK1 phosphorylation in right heart failure PH (Nadadur et al. 2012). Collectively, this shows that PI3K/Akt and MAPK/ERK pathways play a pivotal role in regulating PASMC proliferation and migration and cardiac hypertrophy.
A . B .
C . D .
Figure 1-9: Histopathological changes observed in pulmonary vascular remodelling in human PAH.
Top Left, A: a normal pulmonary artery. Top Right, B: smooth muscle cell hypertrophy and proliferation leading to medial hyperplasia typically observed in mild/moderate human PAH.
Bottom Left, C: adventitial fibrosis observed in moderate PAH. Bottom Right, D: a plexiform lesion characterised by lumen obliteration observed in severe/end-stage PAH. Adapted from (Cool et.al.
2005).
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