Know your enemy: understanding the pathophysiology of pulmonary hypertension

Recognized yearly on May 5th, World Pulmonary Hypertension (PH) Day is an annual global event initiating a month of activities to increase awareness of and advocacy for access to PH diagnosis, treatment, and care. In an accompanying editorial in this issue of the American Journal of Physiology-Lung Cellular and Molecular Physiology, Drs. Werner Seeger and Paul Corris of the Pulmonary Vascular Research Institute (PVRI), President and Chair of the Board, respectively, draw attention to the global impact of PH and highlight goals and priorities of the PVRI to advance research, education, advocacy, and treatment for pulmonary vascular disease (1). The purpose of this companion editorial is to bring added perspective by highlighting some select historical and recent findings that broadened our understanding of the pathophysiology of various forms of PH and perhaps point to avenues for exploration of new therapeutics.

As noted by Drs. Corris and Seeger, PH is an umbrella diagnosis for a condition arising from various etiologies and presenting with differing clinical features (1). The World Health Organization (WHO) classifies PH into five general groups: 1) pulmonary arterial hypertension (PAH), including idiopathic, heritable, connective tissue-associated and infection- or drug/toxin-induced PH; 2) PH due to left heart disease; 3) PH due to lung diseases and/or hypoxia, including high-altitude and chronic obstructive pulmonary disease; 4) PH due to pulmonary obstructions, including chronic thromboembolic disease; and 5) PH with unclear and/or multifactorial origin, including hematologic and systemic disorders. Seminal studies identifying a causal role of hypoxia in PH (7) and decades of subsequent research provided important information as to the structural changes in the pulmonary circulation contributing to the increase in pulmonary vascular resistance under these conditions and identified several cellular signaling pathways involved in the process [reviewed in (14, 17)]. While early studies primarily focused on the effects on adult animals, subsequent work defined the consequences of perinatal hypoxic exposure, which can lead to persistent PH of the newborn and additional sequelae later in life [reviewed in (4)].

As hypoxia was one of the first causes of PH to receive substantial attention, exposure to chronic hypoxia initially was used in preclinical studies to model all PH. However, the pathology of various forms of PH can be quite distinct, likely owing to differing etiologies. For example, pulmonary vascular remodeling in response to hypoxia is primarily characterized by mild to moderate medial and adventitial thickening, whereas robust thickening of all arterial wall layers and development of lesions that fully occlude the lumen are typical hallmarks of PAH. As the field was making strides to understand mechanisms involved in PH associated with hypoxia, less progress was occurring with respect to other forms of PH due to the lack of good animal models and scarce access to tissues from patients. The recognition that severe pulmonary hypertension could be found in families suggested that genetics were likely to play a role in susceptibility. A breakthrough came with the identification of the first mutations associated with the development of PAH, occurring in the bone morphogenetic protein receptor type II (BMPR2) gene [reviewed in (12)]. While BMPR2 mutations account for a large number of heritable PAH cases, subsequent work identified mutations in a number of additional genes, including KCNK3, ATP13A3, AQP1, SOX17, and GDF2, that are associated with PAH [reviewed in (12)]. Exploration of human populations residing at high altitude also revealed genetic adaptation, with mutations in various components of pathways controlling the system regulating activation/degradation of the hypoxia-inducible factor (HIF) transcription factors being associated with protection or susceptibility to PH associated with living in hypoxic environments (15). Whether genetic mutations underlie susceptibility to other forms of PH is unclear, but it represents a potential area for future research efforts.

In addition to genetic factors, it has long been recognized that female sex was a risk factor for PAH [reviewed in (10)]. Interestingly, despite a higher prevalence of PAH in females, several studies have now revealed that male sex was associated with reduced response to therapies and worse outcomes (10), a scenario described as the “estrogen-paradox” in PAH. In contrast to PAH, female sex is protective against development of PH in response to hypoxia in most animals. Further elucidating the complex role sex hormones play in the susceptibility and progression of PH, and in the response to therapy, is an area of active investigation.

Early work demonstrating increased levels of the circulating vasoconstrictor, endothelin-1 (ET-1), and reduced production/activity of vasodilators, such as nitric oxide (NO) and prostacyclin (PGI₂), led to the initial therapies approved for clinical use; unfortunately, these drugs manage and slow progression of PH, but they are not curative. Despite extensive research, however, ET-1 receptor antagonism and drugs that target the NO or PGI₂ pathway remain the mainstay of treatment. The development of novel drug therapies rests, in part, on the ability of investigators to decode the cellular mechanisms underlying the processes involved in the major component contributing to increased pulmonary vascular resistance: vascular remodeling. The mechanisms underlying enhanced vascular cell proliferation, migration, and resistance to apoptosis have remained incompletely understood. Studies identified endothelial dysfunction, downregulation of K⁺ channels, and induction of HIFs early on [reviewed in (17)]. Altered intracellular Ca²⁺ handling in pulmonary vascular cells appears to be a common feature of PH contributing to the changes in cell phenotype, with channels formed by transient receptor potential family proteins and/or ORAI1 creating a main entryway for increasing vascular cell intracellular calcium levels (5, 13). More recent advances describe abnormalities in mitochondrial function and cellular metabolism (3, 9, 11, 16), which are associated with enhanced proliferation, migration and survival, and endothelial-to-mesenchymal transition (18, 19). Based on factors identified from preclinical studies, several promising new therapies are being tested that target epigenetic and/or transcriptional regulation of cell responses (i.e., histone deacetylase inhibitors, HIF inhibitors), metabolism (metformin), and inflammation (i.e., rituximab) (2, 8, 16).

For the better part of three decades, PH research into the mechanisms of disease was limited primarily to PAH and PH associated with hypoxia. However, several exciting developments over the past decade increased the speed and scope of discovery. For example, the development of novel models for Group 1 (i.e., schistosomiasis), Group 2 (i.e., heart failure with preserved ejection fraction), and Group 4 (i.e., chronic thromboembolic disease) PH opened new avenues of study and provided exciting findings regarding potential therapies and molecular abnormalities in these forms of PH. Access to rare patient tissues has increased dramatically, driven in large part by the creation in 2006 of the Pulmonary Hypertension Breakthrough Initiative (PHBI) by the Cardiovascular Medical Research and Education Fund. The PHBI has proved a valuable resource for investigators to obtain samples, including tissues, DNA, RNA, and cells, from patients with various forms of PH for their research studies. In addition, development of novel approaches to further expand studies of defective cellular signaling in patients, such as blood outgrowth cells (6), provides a platform for future discovery and the promise of rapid, even individualized, screening for drug efficacy.

In the fight to find a cure for PH, the old adage remains true—battles can only be won if you know your enemy. Aided by cooperation with the PVRI and the PHBI, accumulating knowledge of the underlying genetics, molecular phenotypes, and pathobiology of all forms of PH is equipping clinicians and investigators with valuable ammunition for drug discovery and eventual tailored therapy. This year, as we observe World PH day, we also thank the PVRI, the PHBI, investigators on the front line of discovery, and healthcare providers who are all working to reduce the burden of pulmonary vascular disease and offer a source of hope to patients across the globe.

GRANTS

This work was funded by National Institutes of Health National Heart, Lung, and Blood Institute Grant HL073859.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author.

AUTHOR CONTRIBUTIONS

L.A.S. drafted manuscript, edited and revised manuscript; and approved final version of manuscript.