The loss of ten‐eleven translocation (TET2) methylcytosine dioxygenase expression contributes to the pathobiology of pulmonary arterial hypertension (PAH). However, whether the expression and activity of other TETs and DNA methyltransferases (DNMTs) are altered in PAH remains enigmatic. Therefore, our objective was to determine the expression of DNMT (1, 3a, and 3b) and TET (1, 2, and 3) and their total activity. We assessed the expression of DNMT and TET enzymes in the leukocytes and their activity in extracellular vesicles (EVs). Expression of DNMT (1, 3a, and 3b), TET (2 and 3) in leukocytes, and total activity in EVs, from PAH patients was higher than in healthy controls. Additionally, we noticed there were difference in expression of these epigenetic enzyme based on ethnicity and found higher DNMT1 and lower TET2/TET3 expression in Caucasian than Hispanic/African American (combine) patients. Since loss‐of‐function mutation(s) and down‐regulation of TET enzymes are associated with hematological malignancies and cytokine production, we determined the expression of genes that encode cytokines in samples of Caucasian and Hispanic/African American patients. Expression of IL6, CSF2, and CCL5 genes were higher in the leukocytes of Caucasian than Hispanic/African American patients, and CSF2 and CCL5 negatively correlated with the decreased expression of TET3. Interestingly, the expression of gene encoding CD34, a marker of myeloid and lymphoid precursor cells, and CD163, a monocyte/macrophage protein, was higher in the leukocytes of Caucasian than Hispanic/African American patients. Furthermore, Hispanic/African American patients having higher TET2/TET3 expression had higher pulmonary capillary wedge pressure. In conclusion, our results revealed higher DNMT1 and lower TET2/TET3 in Caucasian than Hispanic/African American patients together potentially augmented genes encoding inflammation causing cytokines, and CD34+‐derived immunogenic cells, and the severity of PAH.

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It is recently discovered that the cyclic nucleotide, cyclic adenosine monophosphate (cAMP) can be enriched in the extracellular vesicles (EVs) isolated from endothelial cells. In the current perspective a historical context for the discovery of the extracellular cAMP is provided. The story of extracellular cAMP through investigations addressing the molecule's role in the adenosine pathway is followed, which is widespread in mammalian physiology. The adenosine pathway mediates normal physiological conditions such as renin release, phosphate transport, etc., and participates in pathological conditions such as bronchoconstriction of the airways. Furthermore, adenosine mediated biological pathways are regulated via the receptor mediated intracellular cAMP pathway in mammalian cells. It then speculates on the question of whether cAMP enriched EVs could bypass typical receptor mediated cell signaling and directly activate cAMP signaling cascade in target cells. Preliminary studies to suggest cAMP enriched EVs are provided, added to naïve endothelial cells, results in an increase in intracellular cAMP. An alternate mechanism is proposed, apart from the traditional adenosine pathway, that extracellular cAMP may exert its effects and put into perspective how it might consider circulating cAMP moving forward.

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