It is the opening question to a thousand philosophical debates: which came first—the chicken or the egg? Interestingly, almost every discipline imaginable has a proposed solution to this ancient problem: scientists approach this question from an evolutionary point of view, social scientists it through the lens of human cause and effect, and agnostics throw their hands up and declare that nothing is knowable. 

All humor aside, the question of whether pathology precipitates pathology or is the cause of it remains an area of hot debate in many diseases. The problem often goes like this: medical researchers observe that a pathological pathway has been triggered in a disease, often leading to a cascade of other pathological pathways that result in the phenotype of said disease. The question is, do we assume that the first observed aberrant pathway is the cause of the disease and thus attempt to cure it? Or could there be a truer cause waiting to be discovered? 

A Trigger Initiating PAH?

This is the subject of a study written by Kurakula et al titled “Endothelial dysfunction in pulmonary hypertension: cause or consequence?” An intriguing title indeed that acts as a prelude to a fascinating discussion: they wrote, “Although our understanding of the causes for abnormal vascular remodeling in pulmonary arterial hypertension (PAH) is limited, accumulating evidence indicates that endothelial cell dysfunction is one of the first triggers initiating this process.”


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Read more about PAH etiology

The standard wisdom is that endothelial dysfunction plays a role somewhere along the equation in terms of PAH pathology. Ranchoux et al wrote that a “combination of genetic and environmental factors” leads to “endothelial cell injury and impaired vascular regeneration, resulting in aberrant vascular remodeling and loss of small pulmonary arteries.” 

Evans and colleagues wrote, “Many characteristics of PAH are consequences of dysfunctional endothelial cell signaling; these characteristics include pulmonary inflammation and coagulation, oxidative/nitrative stress, altered vascular cell viability (eg, apoptosis-resistance), proliferation, metabolic shift, and accumulations of inflammatory cells and fibroblasts.” 

A Key Transition

Let’s return to the work of Kurakula and colleagues and try to understand where they think endothelial dysfunction plays the most crucial role in PAH pathogenesis. They wrote about a documented phenomenon known as endothelial to mesenchymal transition. When this occurs, “endothelial cells lose cell-cell contact, change their morphology, and adopt a highly migratory and invasive phenotype, thereby losing features of a healthy endothelium,” they wrote. 

Ranchoux and colleagues shed further light on endothelial-to-mesenchymal transition in PAH.

“During [endothelial-to-mesenchymal transition, endothelial cells] lose their junctions to the endothelium and gain migratory and proliferative capacities as they gradually switch from endothelial to a mesenchymal phenotype,“ they explained. “Recently, [endothelial-to-mesenchymal transition] has emerged as a critical player not only in the pathogenesis of tissue fibrosis but also in the pulmonary vascular remodeling processes seen in PAH.”

In other words, endothelial-to-mesenchymal transition drives certain pathological processes forward in PAH. 

Read more about PAH epidemiology 

In addition, Kurakula et al wrote about the role of endothelial cell apoptosis in the development of PAH: “The hypothesis is that disturbed responses to vascular endothelial growth factor (VEGF) signaling, in combination with hypoxia, cause an initial increase in apoptosis in pulmonary arterial endothelial cells, leading to the emergence of aggressive apoptosis resistant and hyperproliferative endothelial cells that cause the formation of intimal lesions.” 

A Growing Interest in Epigenetics

Another interesting field of research with regards to PAH that has gained prominence in recent years is epigenetics.

“Currently, the main focus of study for targeting PAH is the following three mechanisms of epigenetic regulation: DNA methylation, histone modifications, and RNA interference,” Kurakula and colleagues wrote. 

Let’s briefly go through each one. DNA methylation profiling of pulmonary arterial endothelial cells from PAH patients has demonstrated differences in the expression of genes that play a role in inflammation, remodeling, and lipid metabolism. An increase in histone acetylation is associated with PAH vascular remodeling. As for endothelial-specific RNA interference in PAH, Ranchoux and colleagues wrote that a subset of miRNAs have been directly linked to endothelial cell-type dysfunction in PAH. 

Future Perspectives 

The inescapable fact about PAH is that there is still no definitive cure.

“Therefore, research on endothelial cell dysfunction and its stimuli to target structural changes that narrow lumen size in PAH is vital to finding a cure,” Karakula et al wrote. 

Evans and colleagues provided a practical to-do list on the kinds of therapeutic developments we can achieve through a better understanding of PAH endothelial dysfunction: “Novel PAH treatments could aim to: (a) inhibit endothelial cellular injury/apoptosis in the early stages of disease and promote endothelial cellular regeneration and repair; (b) inhibit apoptosis-resistant endothelial cell hyperproliferation; (c) target the endothelial cell secretome; (d) inhibit endothelial-to-mesenchymal transition; or (e) target endothelial-cell derived oxidative/nitrative stress.” 

References

Kurakula K, Smolders VFED, Tura-Ceide O, Jukema JW, Quax PHA, Goumans MJ. Endothelial dysfunction in pulmonary hypertension: cause or consequence? Biomedicines. Published online January 9, 2021. doi:10.3390/biomedicines9010057

Ranchoux B, Harvey LD, Ayon RJ, et al. Endothelial dysfunction in pulmonary arterial hypertension: an evolving landscape (2017 Grover Conference Series)Pulm Circ. 2018;8(1):2045893217752912. doi:10.1177/2045893217752912

Evans CE, Cober ND, Dai Z, Stewart DJ, Zhao YY. Endothelial cells in the pathogenesis of pulmonary arterial hypertensionEur Respir J. Published online September 2, 2021. doi:10.1183/13993003.03957-2020