X-ray of lung

Pulmonary arterial hypertension (PAH) is a rather odd name for a disease, given that it describes outcome rather than etiology. The name in itself is a testament to how little we know about this rare disease. Patients who have PAH usually present with nonspecific cardiac symptoms (eg, fatigue, chest pain, and edema), and the disease is usually diagnosed only after a thorough investigation. 

The main therapies for PAH center around pulmonary vasodilation, which is accomplished by targeting 3 well-understood metabolic pathways: the endothelin-1, nitric oxide (NO)-cyclic guanine monophosphate (cGMP), and cyclic adenosine monophosphate (cAMP) pathways. Pulmonary vasodilation lowers the pulmonary arterial pressure, thereby improving clinical outcomes. 

However, the 5-year survival rate remains low, at a mere 60%. The next option when PAH therapies fail is lung transplant, fraught with its own risks and dangers. 


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Read more about PAH epidemiology

Whenever existing therapies fail, we are faced with 2 possible courses of action: either concede defeat or admit that much remains that we do not understand about a disease, in the hope that through research and perseverance we may come up with therapeutics that better address the root of the problem. Needless to say, the second option has served humanity well and is therefore the one that researchers are pursuing.

French researchers have proposed that an overlooked aspect of PAH is the phenotypic diversity of vascular smooth muscle cells (SMCs). They summarized what we currently know about the behavior of SMCs in an article published in the journal Chest, in the hope that scientists will focus on producing therapies that directly address SMCs and so improve the survival rates and quality of life of patients with PAH. Here, we explore their findings in detail. 

Pathophysiology of PAH

PAH is characterized by dynamic, progressive, and maladaptive pulmonary vascular remodeling, which eventually leads to right-sided heart failure and death. The media of the pulmonary vessels typically undergoes neo-muscularization and thickening, and these abnormalities are distributed uniformly across both lungs, accompanied by perivascular inflammatory infiltration. 

“Although the exact pathophysiology of PAH is still unknown, recent advances provide a better understanding of the three driving components of vascular remodeling: pulmonary endothelial dysfunction, vascular smooth muscle abnormalities, and dysregulation of the inflammatory and immune systems,” wrote the authors of the study. 

We are gaining a greater understanding of how vascular smooth muscle abnormalities contribute to the pathophysiology of PAH. We know that the vascular SMCs of the pulmonary circulation are heterogeneous; the diversity of vascular SMCs along the pulmonary vascular bed can explain the varied local responses to stimuli and pathological conditions. 

In PAH, as pulmonary vascular remodeling occurs, the various contractile vascular cells of the arterial wall acquire a modified, pro-proliferative, apoptosis-resistant phenotype. These various cell types display certain intrinsic abnormalities, such as dysfunction of bone morphogenetic protein receptor type II (BMPRII) signaling, which is associated with disruption of the DNA damage response pathway and the slow buildup of unrepaired DNA lesions. 

Read more about PAH complications

The intrinsic abnormalities of the different vascular contractile cell types in PAH are also associated with an excessive response to growth factor-stimulating pathways. This response causes heightened signal transduction and altered protein expression in the integration or amplification of intracellular signaling pathways. 

Also in PAH, vascular contractile cells are able to adapt their metabolic status, such as by switching from mitochondrial oxidative phosphorylation to glycolysis, thus causing the dysregulation of important metabolic pathways, including those related to amino acid metabolism and lipid oxidation. Another abnormality may be heightened signaling of hypoxia-inducible factors (HIFs). These metabolic changes damage the lungs; for example, studies in mice have shown that the dysregulation of fatty acid oxidation can result in acute hypoxic pulmonary vasoconstriction. 

In addition, cell-to-cell communication breaks down in PAH, resulting in the loss of important vascular functions, such as the ability to adapt to changes in the local pulmonary arterial microenvironment. Pulmonary endothelial dysfunction causes a loss of balance between vasodilators and vasoconstrictors in the pulmonary circulation, so that a functional vascular network cannot be maintained and vascular tissue homeostasis is severely disrupted. 

Research tells us that inflammation often precedes vascular remodeling, which means that there is a good chance that some interaction between vascular contractile cells and immune cells occurs in PAH. However, it is still unclear exactly how these interactions take place, so that the development of immunotherapies for PAH is limited. 

Senescent cells are often associated with damaging morphological and metabolic changes, and the same is true for senescent vascular SMCs in PAH. “Senescent vascular SMCs are emerging as key drivers of chronic vascular inflammation and lung destruction in age-related respiratory disorders, including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD),” the authors of the study wrote. 

New Therapeutic Possibilities 

The fruits of research on the pathophysiology of PAH have opened up a new world of therapeutic possibilities, with each dysfunctional pathway a possible target for new drugs. For example, scientists can focus on breaking the link between inflammation and pulmonary vascular pathways by creating targeted anti-inflammatory medication. Similarly, the dysfunctional BMPRII pathway can be targeted to reduce disruption of the DNA damage response pathway. 

Current PAH therapies “predominantly target endothelial dysfunction,” according to the authors of the study. With a deeper understanding of the pathophysiology of PAH at the cellular level, researchers may finally be poised to create new therapies that may change the entire treatment landscape of PAH, to the benefit of patients everywhere with this disease.

References

Lechartier B, Berrebeh N, Huertas A, Humbert M, Guignabert C, Tu L. Phenotypic diversity of vascular smooth muscle cells in pulmonary arterial hypertension: implications for therapy. Chest. 2021:S0012-3692(21)03667-9. doi:10.1016/j.chest.2021.08.040

Huertas A, Tu L, Humbert M, Guignabert C. Chronic inflammation within the vascular wall in pulmonary arterial hypertension: more than a spectator. Cardiovasc Res. 2020;116(5):885-893. doi:10.1093/cvr/cvz308