Did You Know

…. that the pathobiology of pulmonary arterial hypertension (PAH) has neoplastic features?Pulmonary arterial hypertension is a disease of the small pulmonary arteries, characterized by vascular narrowing leading to progressive elevations in artery pressures and, ultimately, right heart failure¹.  In 1891, Von Romberg discovered pulmonary vascular lesions, which he named “pulmonary vascular sclerosis”².  In PAH, vascular lesions involve a distinct constellation of lesions known clinically as “plexogenic pulmonary arteriopathy”. One of the arteriopathies, the plexiform lesion (Figure 1), is considered the histological hallmark of this arteriopathy³.  However, the etiology of this vascular lesion remains controversial. 
Vascular lesions involve three components: smooth muscle layer, adventitia and  endothelium⁴.  However, much of the research performed over the years has focused on the smooth muscle component. This was due to studies with rats exposed to either chronic hypoxia or treated with monocrotaline that suggested pulmonary vasoconstriction as the cause of vascular remodeling⁵.  Although investigations into this vasoconstrictive theory of PAH have yielded a number of drugs currently used to treat the disease, it has now been shown that less than 10% of PAH patients respond to vasodilators⁶.  Thus, the development of new theories has become necessary.  In 1994, Tuder using immunohistochemistry, described augmented endothelial cell proliferation leading to formation of complicated capillary-like channels (angio-proliferation) as the main component of the plexiform lesion⁷.    In 1998, the discovery of endothelial monoclonality in plexiform lesions of primary pulmonary hypertension4 led Voelkel and collaborators to formulate the neoplastic hypothesis of the disease⁵.
Neoplasia is an abnormal proliferation of cells that results in tumor formation without metastasis. Two important events occur during tumor formation: uncontrolled angio-proliferation and inhibition of apoptosis^{5, 6}.  In the last 15 years of research, several mutations have been linked to both events in endothelial cells from plexiform lesions. For instance, alterations in transforming growth factor-β (TGF-β) receptor II may render endothelial cells insensitive to the cell growth-controlling effects of TGF-β5.  Interestingly, mutations in bone morphogenic protein receptor II (BMPRII), a member of the TGF-β receptor family, are responsible for the familial forms of PAH1.  Moreover, expression of the anti-apoptotic protein survivin, which inhibits activation of  caspases 3 and 7, has been reported in PAH plexiform lesions⁴.  Consistent with these findings, endothelial cells isolated from pulmonary arteries of patients with PAH are hyperproliferative and apoptosis-resistant⁵.  
In addition to mutations conferring apoptosis resistance, tumor cells suppress mitochondrial function⁶.  As a consequence, a shift from oxidative phosphorylation to aerobic glycolysis occurs, which is known as the Warburg effect⁸. The Warburg effect, originally described in tumor cells, is characterized by decreased oxygen consumption and increased glucose uptake. This glycolytic phenotype has been associated with resistance to apoptosis⁶ and is common to proliferating cells⁸. Recently, the Warburg effect has been described in pulmonary artery endothelial cells from patients with PAH⁹. Clinically, the most striking evidence supporting the neoplastic hypothesis and the involvement of the Warburg effect is a study using positron emission tomography scan in PAH patients⁹. This technique is utilized to detect tumors, based on the faculty of tumor cells to actively consume glucose at high rates. Higher fluoro-deoxy-D-glucose (labeled glucose analog) uptake was found in PAH lungs compared with healthy controls⁹, indicative of the Warburg effect. 
Current therapies used in the treatment of PAH have limited effectiveness and do not prevent mortality. Most of these therapies are targeted against the vasoconstriction component of PAH.  Furthermore, diagnosis of the disease requires invasive techniques.  Exploration into the neoplastic theory of PAH opens the door to develop new diagnostic techniques and targeted therapies against the vascular remodeling component.
Glenda Parra-Bonilla.

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