The Biological Mechanisms Behind Pulmonary Hypertension
April 9th, 2026
Pulmonary hypertension (PH) is a complex condition characterised by elevated pulmonary arterial pressure, arising from structural and functional alterations within the pulmonary vasculature. Much of what is known about the pathophysiological mechanisms underlying the development and progression of PH comes from studies on Group 1 PH pulmonary arterial hypertension (PAH). However, it is likely that similar processes may contribute, to varying degrees, in other PH subgroups.
Although the aetiologies of PH subgroups differ, several core biological mechanisms have been identified. These include endothelial dysfunction, pulmonary vascular remodelling, vasoconstriction (narrowing of blood vessels), in situ thrombosis (clot formation within the vessels), and increased pulmonary vascular resistance. Collectively, these processes lead to progressive obstruction of pulmonary blood flow and increased strain on the right ventricle.
Understanding the biological processes that underlie PH is essential for guiding effective treatment strategies. This blog provides an overview of the key pathophysiological mechanisms that have been identified, highlighting how they contribute to disease progression and clinical outcomes in PH.
Endothelial Dysfunction
Endothelial dysfunction is considered an initiating event in the pathogenesis and development of PH. The endothelium, composed of a monolayer of endothelial cells (ECs), lines the innermost surface of the pulmonary artery, where they form a barrier between the blood and other layers of the artery walls. In PH, these ECs exhibit impaired production of vasodilatory and antiproliferative mediators, including reduced nitric oxide (NO) and prostacyclin, alongside increased expression of vasoconstrictors such as endothelin-1 (ET-1) [1,2].
This imbalance promotes sustained vasoconstriction and contributes to vascular remodelling. Dysfunctional endothelial cells also release growth factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF2) and platelet-derived growth factor (PDGF), which stimulate the proliferation and migration of ECs, smooth muscle cells, and fibroblasts. Over time, these changes result in thickening and stiffening of the pulmonary arterial walls [3].
Additionally, oxidative stress, driven by excessive reactive oxygen species, may also further impair endothelial function and promote smooth muscle proliferation, inflammation, and thrombosis, thereby exacerbating vascular remodelling [4–6].
Vascular Remodelling and Plexiform Lesions
Endothelial dysfunction, combined with abnormal cellular proliferation, inflammation, and apoptosis resistance, drives structural remodelling of the pulmonary vasculature [6]. In PAH, these processes can lead to the formation of complex vascular lesions, known as plexiform lesions, which are a common pathological hallmark of the disease and contribute to progressive arterial lumen obstruction.
Additionally, endothelial-to-mesenchymal transition contributes to fibrosis and further vessel stiffening. Inflammatory mediators, including proinflammatory cytokines (Interleukin (IL)-1β, IL-6, tumour necrosis factor alpha (TNF-α)) and chemokines (Monocyte Chemoattractant Protein-1 (MCP-1), IL-8), recruit immune cells (monocytes and lymphocytes) to the vessel wall, amplifying remodelling and obstruction [2,3]. Prothrombotic factors such as tissue factor (TF), von Willebrand factor (vWF), and plasminogen activator inhibitor-1 (PAI-1) promote platelet activation and in situ thrombosis, further restricting pulmonary blood flow [2,3].
Hemodynamic Consequences
As vascular modelling progresses, pulmonary vascular resistance increases, imposing chronic pressure overload on the right ventricle. Compensatory right ventricular hypertrophy initially maintains cardiac output. Still, persistent strain eventually leads to right ventricular dilation, dysfunction, and right heart failure, the leading cause of death in patients with PH [1,3].
A comprehensive understanding of these pathophysiological mechanisms informs current therapeutic strategies in PH. Current therapies for PAH, for example, target the nitric oxide, endothelin, and prostacyclin pathways identified in these mechanisms. By mapping therapies to specific pathways, clinicians can address vasoconstriction, endothelial dysfunction, and vascular remodelling more effectively. Future research into these mechanisms may lead to the development of more targeted and effective treatments across all forms of PH.
References
[1] Huber L, Bye H, Brock M. The pathogenesis of pulmonary hypertension – an update. Swiss Med Wkly. 2015; doi: 10.4414/smw.2015.14202.
[2] Budhiraja R, Tuder RM, Hassoun PM. Endothelial Dysfunction in Pulmonary Hypertension. Circulation. 2004;109(2):159–165.
[3] Wilkins MR. Pulmonary hypertension: the science behind the disease spectrum. European Respiratory Review. 2012;21(123):19–26.
[4] Schulz E, Gori T, Münzel T. Oxidative stress and endothelial dysfunction in hypertension. Hypertension Research. 2011;34(6):665–673.
[5] Yung L, Leung F, Yao X, et al. Reactive Oxygen Species in Vascular Wall. Cardiovascular & Hematological Disorders-Drug Targets. 2006;6(1):1–19.
[6] Fortuño A, José GS, Moreno MU, et al. Oxidative stress and vascular remodelling. Exp Physiol. 2005;90(4):457–462.