Pulmonary Hypertension: What Are the Underlying Mechanisms?
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Published
Feb 28, 2025
Abstract
Pulmonary hypertension is a multifaceted condition defined by elevated blood pressure within the pulmonary arteries, which may result in significant injury and stress on the heart. The fundamental mechanisms underlying pulmonary hypertension are complex and encompass a range of factors, including vasoconstriction, vascular remodeling, inflammation, and endothelial dysfunction. Vasoconstriction transpires when the smooth muscle cells within the pulmonary arteries undergo abnormal contraction, resulting in the constriction of the blood vessels and a subsequent limitation of blood flow. Vascular remodeling pertains to the structural alterations occurring within the vessel walls, encompassing thickening and stiffening, which may subsequently lead to increased pressure levels. Inflammation serves a pivotal function in initiating immune responses that can result in the deterioration of arterial walls. Endothelial dysfunction refers to the compromised functionality of the endothelium that lines the blood vessels, which adversely impacts their capacity to modulate blood flow and pressure. These fundamental mechanisms frequently operate concurrently to intensify pulmonary hypertension, underscoring the necessity of addressing multiple pathways in its therapeutic management.
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Keywords
Pulmonary Hypertension, Mechanisms, Pathophysiology, Prognosis, Outcomes
Supporting Agencies
No funding source declared.
References
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Budhiraja, R., Tuder, R. M., & Hassoun, P. M. (2004). Endothelial dysfunction in pulmonary hypertension. Circulation, 109(2), 159–165. https://doi.org/10.1161/01.cir.0000102381.57477.50
Cheng, Z., & Zhang, J. (2024). Exploring the role of Gut-Lung interactions in COPD pathogenesis: A comprehensive review on microbiota characteristics and inflammation modulation. Chronic Obstructive Pulmonary Diseases Journal of the COPD Foundation, 11(3), 311–325. https://doi.org/10.15326/jcopdf.2023.0442
Dorfmüller, P., Chaumais, M., Giannakouli, M., Durand-Gasselin, I., Raymond, N., Fadel, E., Mercier, O., Charlotte, F., Montani, D., Simonneau, G., Humbert, M., & Perros, F. (2011). Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension. Respiratory Research, 12(1). https://doi.org/10.1186/1465-9921-12-119
Fares, W., & Bazan, I. (2015). Pulmonary hypertension: diagnostic and therapeutic challenges. Therapeutics and Clinical Risk Management, 1221. https://doi.org/10.2147/tcrm.s74881
Friedman, S. E., & Andrus, B. W. (2012). Obesity and Pulmonary Hypertension: A review of Pathophysiologic Mechanisms. Journal of Obesity, 2012, 1–9. https://doi.org/10.1155/2012/505274
Garcia, M. R., Comstock, B. A., Patel, R. M., Tolia, V. N., Josephson, C. D., Georgieff, M. K., Rao, R., Monsell, S. E., Juul, S. E., Ahmad, K. A., Mayock, D. E., Wadhawan, R., Courtney, S. E., Robinson, T., Bendel-Stenzel, E., Baserga, M., LaGamma, E. F., Downey, L. C., Fahim, N., . . . Widness, J. (2022). Iron supplementation and the risk of bronchopulmonary dysplasia in extremely low gestational age newborns. Pediatric Research, 93(3), 701–707. https://doi.org/10.1038/s41390-022-02160-2
Girgis, R. E., & Mathai, S. C. (2007). Pulmonary Hypertension Associated with Chronic Respiratory Disease. Clinics in Chest Medicine, 28(1), 219–232. https://doi.org/10.1016/j.ccm.2006.11.006
Gomberg-Maitland, M., & Olschewski, H. (2008). Prostacyclin therapies for the treatment of pulmonary arterial hypertension. European Respiratory Journal, 31(4), 891–901. https://doi.org/10.1183/09031936.00097107
Gomez, J. A. (2021). Renin angiotensin aldosterone system functions in renovascular hypertension. In IntechOpen eBooks. https://doi.org/10.5772/intechopen.97491
Humbert, M., Guignabert, C., Bonnet, S., Dorfmüller, P., Klinger, J. R., Nicolls, M. R., Olschewski, A. J., Pullamsetti, S. S., Schermuly, R. T., Stenmark, K. R., & Rabinovitch, M. (2018). Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. European Respiratory Journal, 53(1), 1801887. https://doi.org/10.1183/13993003.01887-2018
Hung, J. (2007). Pregnancy Complicated with Maternal Pulmonary Hypertension and Placenta Accreta. Journal of the Chinese Medical Association, 70(6), 257–259. https://doi.org/10.1016/s1726-4901(09)70370-3
Kotlyarov, S. (2022). Involvement of the innate immune system in the pathogenesis of chronic obstructive pulmonary disease. International Journal of Molecular Sciences, 23(2), 985. https://doi.org/10.3390/ijms23020985
Krug, S. (2009). Inhaled iloprost for the control of pulmonary hypertension. Vascular Health and Risk Management, 465. https://doi.org/10.2147/vhrm.s3223
Lai, Y., Potoka, K. C., Champion, H. C., Mora, A. L., & Gladwin, M. T. (2014). Pulmonary arterial hypertension. Circulation Research, 115(1), 115–130. https://doi.org/10.1161/circresaha.115.301146
Lang, I. M., & Palazzini, M. (2019). The burden of comorbidities in pulmonary arterial hypertension. European Heart Journal Supplements, 21(Supplement_K), K21–K28. https://doi.org/10.1093/eurheartj/suz205
Liotti, L., Pecoraro, L., Mastrorilli, C., Castagnoli, R., Saretta, F., Mori, F., Arasi, S., Barni, S., Giovannini, M., Caminiti, L., Del Giudice, M. M., & Novembre, E. (2023). Pediatric Angioedema without Wheals: How to Guide the Diagnosis. Life, 13(4), 1021. https://doi.org/10.3390/life13041021
McLaughlin, V. V., & McGoon, M. D. (2006). Pulmonary arterial hypertension. Circulation, 114(13), 1417–1431. https://doi.org/10.1161/circulationaha.104.503540
Naeije, R., & Barberà, J. A. (2001). Pulmonary hypertension associated with COPD. Critical Care, 5(6), 286. https://doi.org/10.1186/cc1049
Patel, H. P., & Mitsnefes, M. (2005). Advances in the pathogenesis and management of hypertensive crisis. Current Opinion in Pediatrics, 17(2), 210–214. https://doi.org/10.1097/01.mop.0000150769.38484.b3
Patel, S., Rauf, A., Khan, H., & Abu-Izneid, T. (2017). Renin-angiotensin-aldosterone (RAAS): The ubiquitous system for homeostasis and pathologies. Biomedicine & Pharmacotherapy, 94, 317–325. https://doi.org/10.1016/j.biopha.2017.07.091
Petrosillo, N. (2010). Pulmonary vascular disease and infection: a tale of two diseases. Clinical Microbiology and Infection, 17(1), 5–6. https://doi.org/10.1111/j.1469-0691.2010.03291.x
Plecitá-Hlavatá, L., D’alessandro, A., Kasmi, K. E., Li, M., Zhang, H., Ježek, P., & Stenmark, K. R. (2017). Metabolic reprogramming and redox signaling in pulmonary hypertension. Advances in Experimental Medicine and Biology, 241–260. https://doi.org/10.1007/978-3-319-63245-2_14
Rosenblum, W. D. (2010). Pulmonary arterial hypertension. Cardiology in Review, 18(2), 58–63. https://doi.org/10.1097/crd.0b013e3181cd2c9e
Ryu, J. H., Krowka, M. J., Swanson, K. L., Pellikka, P. A., & McGoon, M. D. (2007). Pulmonary hypertension in patients with interstitial lung diseases. Mayo Clinic Proceedings, 82(3), 342–350. https://doi.org/10.4065/82.3.342
Soubrier, F., Chung, W. K., Machado, R., Grünig, E., Aldred, M., Geraci, M., Loyd, J. E., Elliott, C. G., Trembath, R. C., Newman, J. H., & Humbert, M. (2013). Genetics and Genomics of Pulmonary Arterial Hypertension. Journal of the American College of Cardiology, 62(25), D13–D21. https://doi.org/10.1016/j.jacc.2013.10.035
Souza, R., Fernandes, C. J., & Jardim, C. (2009). Other causes of PAH (Schistosomiasis, Porto-Pulmonary hypertension and Hemolysis-Associated pulmonary hypertension). Seminars in Respiratory and Critical Care Medicine, 30(04), 448–457. https://doi.org/10.1055/s-0029-1233314
Stitham, J., Midgett, C., Martin, K. A., & Hwa, J. (2011). Prostacyclin: an inflammatory paradox. Frontiers in Pharmacology, 2. https://doi.org/10.3389/fphar.2011.00024
Sun, W., & Chan, S. Y. (2018). Pulmonary arterial stiffness: an early and pervasive driver of pulmonary arterial hypertension. Frontiers in Medicine, 5. https://doi.org/10.3389/fmed.2018.00204
Sun, Y., Liu, S., Chen, C., Yang, S., Pei, G., Lin, M., Wang, T., Long, J., Yan, Q., Yao, J., Lin, Y., Yi, F., Meng, L., Tan, Y., Ai, Q., Chen, N., & Yang, Y. (2023). The mechanism of programmed death and endoplasmic reticulum stress in pulmonary hypertension. Cell Death Discovery, 9(1). https://doi.org/10.1038/s41420-023-01373-6
Tuder, R. M., Cool, C. D., Geraci, M. W., Wang, J., Abman, S. H., Wright, L., Badesch, D., & Voelkel, N. F. (1999). Prostacyclin Synthase Expression Is Decreased in Lungs from Patients with Severe Pulmonary Hypertension. American Journal of Respiratory and Critical Care Medicine, 159(6), 1925–1932. https://doi.org/10.1164/ajrccm.159.6.9804054
Tuder, R. M., Stacher, E., Robinson, J., Kumar, R., & Graham, B. B. (2013). Pathology of pulmonary hypertension. Clinics in Chest Medicine, 34(4), 639–650. https://doi.org/10.1016/j.ccm.2013.08.009
Wang, Z., & Chesler, N. C. (2011). Pulmonary Vascular Wall Stiffness: An Important Contributor to the Increased Right Ventricular Afterload with Pulmonary Hypertension. Pulmonary Circulation, 1(2), 212–223. https://doi.org/10.4103/2045-8932.83453
Austin, E. D., Lahm, T., West, J., Tofovic, S. P., Johansen, A. K., MacLean, M. R., Alzoubi, A., & Oka, M. (2013). Gender, sex hormones and pulmonary hypertension. Pulmonary Circulation, 3(2), 294–314. https://doi.org/10.4103/2045-8932.114756
Budhiraja, R., Tuder, R. M., & Hassoun, P. M. (2004). Endothelial dysfunction in pulmonary hypertension. Circulation, 109(2), 159–165. https://doi.org/10.1161/01.cir.0000102381.57477.50
Cheng, Z., & Zhang, J. (2024). Exploring the role of Gut-Lung interactions in COPD pathogenesis: A comprehensive review on microbiota characteristics and inflammation modulation. Chronic Obstructive Pulmonary Diseases Journal of the COPD Foundation, 11(3), 311–325. https://doi.org/10.15326/jcopdf.2023.0442
Dorfmüller, P., Chaumais, M., Giannakouli, M., Durand-Gasselin, I., Raymond, N., Fadel, E., Mercier, O., Charlotte, F., Montani, D., Simonneau, G., Humbert, M., & Perros, F. (2011). Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension. Respiratory Research, 12(1). https://doi.org/10.1186/1465-9921-12-119
Fares, W., & Bazan, I. (2015). Pulmonary hypertension: diagnostic and therapeutic challenges. Therapeutics and Clinical Risk Management, 1221. https://doi.org/10.2147/tcrm.s74881
Friedman, S. E., & Andrus, B. W. (2012). Obesity and Pulmonary Hypertension: A review of Pathophysiologic Mechanisms. Journal of Obesity, 2012, 1–9. https://doi.org/10.1155/2012/505274
Garcia, M. R., Comstock, B. A., Patel, R. M., Tolia, V. N., Josephson, C. D., Georgieff, M. K., Rao, R., Monsell, S. E., Juul, S. E., Ahmad, K. A., Mayock, D. E., Wadhawan, R., Courtney, S. E., Robinson, T., Bendel-Stenzel, E., Baserga, M., LaGamma, E. F., Downey, L. C., Fahim, N., . . . Widness, J. (2022). Iron supplementation and the risk of bronchopulmonary dysplasia in extremely low gestational age newborns. Pediatric Research, 93(3), 701–707. https://doi.org/10.1038/s41390-022-02160-2
Girgis, R. E., & Mathai, S. C. (2007). Pulmonary Hypertension Associated with Chronic Respiratory Disease. Clinics in Chest Medicine, 28(1), 219–232. https://doi.org/10.1016/j.ccm.2006.11.006
Gomberg-Maitland, M., & Olschewski, H. (2008). Prostacyclin therapies for the treatment of pulmonary arterial hypertension. European Respiratory Journal, 31(4), 891–901. https://doi.org/10.1183/09031936.00097107
Gomez, J. A. (2021). Renin angiotensin aldosterone system functions in renovascular hypertension. In IntechOpen eBooks. https://doi.org/10.5772/intechopen.97491
Humbert, M., Guignabert, C., Bonnet, S., Dorfmüller, P., Klinger, J. R., Nicolls, M. R., Olschewski, A. J., Pullamsetti, S. S., Schermuly, R. T., Stenmark, K. R., & Rabinovitch, M. (2018). Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. European Respiratory Journal, 53(1), 1801887. https://doi.org/10.1183/13993003.01887-2018
Hung, J. (2007). Pregnancy Complicated with Maternal Pulmonary Hypertension and Placenta Accreta. Journal of the Chinese Medical Association, 70(6), 257–259. https://doi.org/10.1016/s1726-4901(09)70370-3
Kotlyarov, S. (2022). Involvement of the innate immune system in the pathogenesis of chronic obstructive pulmonary disease. International Journal of Molecular Sciences, 23(2), 985. https://doi.org/10.3390/ijms23020985
Krug, S. (2009). Inhaled iloprost for the control of pulmonary hypertension. Vascular Health and Risk Management, 465. https://doi.org/10.2147/vhrm.s3223
Lai, Y., Potoka, K. C., Champion, H. C., Mora, A. L., & Gladwin, M. T. (2014). Pulmonary arterial hypertension. Circulation Research, 115(1), 115–130. https://doi.org/10.1161/circresaha.115.301146
Lang, I. M., & Palazzini, M. (2019). The burden of comorbidities in pulmonary arterial hypertension. European Heart Journal Supplements, 21(Supplement_K), K21–K28. https://doi.org/10.1093/eurheartj/suz205
Liotti, L., Pecoraro, L., Mastrorilli, C., Castagnoli, R., Saretta, F., Mori, F., Arasi, S., Barni, S., Giovannini, M., Caminiti, L., Del Giudice, M. M., & Novembre, E. (2023). Pediatric Angioedema without Wheals: How to Guide the Diagnosis. Life, 13(4), 1021. https://doi.org/10.3390/life13041021
McLaughlin, V. V., & McGoon, M. D. (2006). Pulmonary arterial hypertension. Circulation, 114(13), 1417–1431. https://doi.org/10.1161/circulationaha.104.503540
Naeije, R., & Barberà, J. A. (2001). Pulmonary hypertension associated with COPD. Critical Care, 5(6), 286. https://doi.org/10.1186/cc1049
Patel, H. P., & Mitsnefes, M. (2005). Advances in the pathogenesis and management of hypertensive crisis. Current Opinion in Pediatrics, 17(2), 210–214. https://doi.org/10.1097/01.mop.0000150769.38484.b3
Patel, S., Rauf, A., Khan, H., & Abu-Izneid, T. (2017). Renin-angiotensin-aldosterone (RAAS): The ubiquitous system for homeostasis and pathologies. Biomedicine & Pharmacotherapy, 94, 317–325. https://doi.org/10.1016/j.biopha.2017.07.091
Petrosillo, N. (2010). Pulmonary vascular disease and infection: a tale of two diseases. Clinical Microbiology and Infection, 17(1), 5–6. https://doi.org/10.1111/j.1469-0691.2010.03291.x
Plecitá-Hlavatá, L., D’alessandro, A., Kasmi, K. E., Li, M., Zhang, H., Ježek, P., & Stenmark, K. R. (2017). Metabolic reprogramming and redox signaling in pulmonary hypertension. Advances in Experimental Medicine and Biology, 241–260. https://doi.org/10.1007/978-3-319-63245-2_14
Rosenblum, W. D. (2010). Pulmonary arterial hypertension. Cardiology in Review, 18(2), 58–63. https://doi.org/10.1097/crd.0b013e3181cd2c9e
Ryu, J. H., Krowka, M. J., Swanson, K. L., Pellikka, P. A., & McGoon, M. D. (2007). Pulmonary hypertension in patients with interstitial lung diseases. Mayo Clinic Proceedings, 82(3), 342–350. https://doi.org/10.4065/82.3.342
Soubrier, F., Chung, W. K., Machado, R., Grünig, E., Aldred, M., Geraci, M., Loyd, J. E., Elliott, C. G., Trembath, R. C., Newman, J. H., & Humbert, M. (2013). Genetics and Genomics of Pulmonary Arterial Hypertension. Journal of the American College of Cardiology, 62(25), D13–D21. https://doi.org/10.1016/j.jacc.2013.10.035
Souza, R., Fernandes, C. J., & Jardim, C. (2009). Other causes of PAH (Schistosomiasis, Porto-Pulmonary hypertension and Hemolysis-Associated pulmonary hypertension). Seminars in Respiratory and Critical Care Medicine, 30(04), 448–457. https://doi.org/10.1055/s-0029-1233314
Stitham, J., Midgett, C., Martin, K. A., & Hwa, J. (2011). Prostacyclin: an inflammatory paradox. Frontiers in Pharmacology, 2. https://doi.org/10.3389/fphar.2011.00024
Sun, W., & Chan, S. Y. (2018). Pulmonary arterial stiffness: an early and pervasive driver of pulmonary arterial hypertension. Frontiers in Medicine, 5. https://doi.org/10.3389/fmed.2018.00204
Sun, Y., Liu, S., Chen, C., Yang, S., Pei, G., Lin, M., Wang, T., Long, J., Yan, Q., Yao, J., Lin, Y., Yi, F., Meng, L., Tan, Y., Ai, Q., Chen, N., & Yang, Y. (2023). The mechanism of programmed death and endoplasmic reticulum stress in pulmonary hypertension. Cell Death Discovery, 9(1). https://doi.org/10.1038/s41420-023-01373-6
Tuder, R. M., Cool, C. D., Geraci, M. W., Wang, J., Abman, S. H., Wright, L., Badesch, D., & Voelkel, N. F. (1999). Prostacyclin Synthase Expression Is Decreased in Lungs from Patients with Severe Pulmonary Hypertension. American Journal of Respiratory and Critical Care Medicine, 159(6), 1925–1932. https://doi.org/10.1164/ajrccm.159.6.9804054
Tuder, R. M., Stacher, E., Robinson, J., Kumar, R., & Graham, B. B. (2013). Pathology of pulmonary hypertension. Clinics in Chest Medicine, 34(4), 639–650. https://doi.org/10.1016/j.ccm.2013.08.009
Wang, Z., & Chesler, N. C. (2011). Pulmonary Vascular Wall Stiffness: An Important Contributor to the Increased Right Ventricular Afterload with Pulmonary Hypertension. Pulmonary Circulation, 1(2), 212–223. https://doi.org/10.4103/2045-8932.83453
How to Cite
Lane, M. (2025). Pulmonary Hypertension: What Are the Underlying Mechanisms?. Science Insights, 46(2), 1733–1736. https://doi.org/10.15354/si.25.op253
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