Pulmonary hypertensive arterial disease (PHAD) is a devastating and progressive cardiopulmonary disease with severe endothelial dysfunction. PHAD develops after the threshold pressure in pulmonary arteries at resting state is exceeded. This often results in right ventricular dysfunction and heart failure and is the main cause of mortality in patients with PHAD when untreated (1). PHAD induces vascular remodeling and is characterized by production of new endothelial cells, myofibroblasts, vascular smooth cells, extracellular matrix changes, vascular/perivascular fibrosis induction and inflammation.

This network includes some of the pathological events contributing to PHAD: muscularization of pulmonary vessel, proliferation of PASMC (pulmonary arterial smooth muscle cells), induction of nitric oxide (an important vascular modulator in the development of pulmonary hypertension), and systolic pressure of right ventricle. The role of immune cells involved in inflammatory processes is also shown (generation of bone marrow-derived dendritic cells, quantity of TH2 cells, TH2 immune response and quantity of CD11b+ cells, activation of eosinophils, and activation of helper T lymphocytes and others) (2,3). In particular, the recruitment of macrophages (CD11b+ cells) in perivascular regions of pulmonary arteries has been observed which are present in vascular lesions in patients (3).

A number of genes present in the network have a known association with PHAD as represented in the QKB, namely ACVRL1, APOE, BMPR2, CSF2, EDNRA, EDNRB, EIF2AK4, ENG, EPAS1, FOSL2, GDF2, KCNK3, NOS3, P2RY12, PDE5A, PTGIR, and TNFSF10. Many of these genes are known therapeutic targets for pulmonary hypertension (EDNRA, EDNRB, P2RY12, PDE5A, and PTGIR). Some other genes are major players in PAH, such as BMPR2 and ENG, where loss of function mutations in these genes have been causally linked to PHAD (4,5,6,7). The network also highlights the contribution of BMPR2 and APOE towards increasing the Systolic pressure of the right ventricle a well-known phenotype of PHAD (8).

The network contains several predicted genes (ACVR1, ACVR2A, BMP6, CLK1, CSF3R, ERFE, FBXO11, ICOS, IL18, IRF8, HJV, HSPE1, MED23, NFKBIE, SERPINB2, TGFA, TMPRSS6, TNFSF10A,) that are not associated with PHAD in the QKB. Among this list, a subset of genes is interconnected and potentially contributes to the dysfunction of BMP signaling in PHAD. For example, ACVR1, ACVR2A, and BMP6 are connected to the BMP signaling pathway, as BMP6 can bind receptors BMPR2 and ACVR2A, and all these genes are expressed in vascular smooth muscles cells including pulmonary arterial smooth muscle cells (QKB findings). Members of the TNF family (such as the predicted TNFSF10A) could be detrimental, as TNF has been shown to suppress the BMP signaling and to induce BMP6-mediated PASMC proliferation via preferential activation of ACVR2a signaling (9).

Other predicted players in the pathogenesis of PHAD include IL-18, whose inhibition has been shown to suppress pulmonary hypertension in a mouse model (10). Moreover, increased expression of IL-18 may accentuate the inflammatory setting leading to vascular obstruction characteristic of PAH (11). Finally, it has been shown very recently that SERPINB2 is downregulated in PHAD patients, and its activity reduces the disease development, pointing to SERPINB2 as a potential therapeutic target for PHAD (12).

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3. Microenvironmental Regulation of Macrophage Transcriptomic and Metabolomic Profiles in Pulmonary Hypertension. Li M, et al. Front Immunol. 2021,12:640718. PMID: 33868271
4. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. International PPH Consortium, Lane KB, et al. Nat Genet. 2000, (1):81-4. PMID: 10973254
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6. Molecular pathogenesis of pulmonary arterial hypertension. Rabinovitch M. J Clin Invest. 2012, 122(12):4306-13. PMID: 23202738
7. Bone morphogenetic protein receptors: Structure, function and targeting by selective small molecule kinase inhibitors. Sanchez-Duffhues G, et al. Bone. 2020, 138:115472. PMID: 32522605
8. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Hansmann G, et al. Circulation. 2007, 115(10):1275-84. PMID: 17339547
9. TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Hurst LA, et al. Nat Commun. 2017, 8:14079. PMID: 28084316
10. Interleukin-18 disruption suppresses hypoxia-induced pulmonary artery hypertension in mice. Morisawa D, et al. Int J Cardiol. 2016, 202:522-4. PMID: 26440469
11. Type I immune response cytokine-chemokine cascade is associated with pulmonary arterial hypertension. Ross DJ, et al. J Heart Lung Transplant. 2012, (8):865-73. PMID: 22658713
12. Plasminogen activator Inhibitor-2 inhibits pulmonary arterial smooth muscle cell proliferation in pulmonary arterial hypertension via PI3K/Akt and ERK signaling. Zhang S, et al. Exp Cell Res. 2021, 398(1):112392. PMID: 33227315