Overview: pulmonary vascular function in health and disease

The lung is a remarkable organ in many respects, not the least of which are the specific and extraordinary attributes of the pulmonary circulation. Despite this, the pulmonary vasculature has received much less attention than the systemic circulation from authors in The Journal of Physiology. In 2017, approximately 600 original research articles, perspectives, reviews, letters and editorials were published in The Journal of Physiology and a quick search of these publications revealed that only 28 of these manuscripts were related to the lung or respiratory system, with only 2 original research articles focused on the pulmonary circulation. It is against this background that this Special Issue was conceived to highlight to the general readership the recent advances made by cardiopulmonary and vascular physiologists in the understanding of molecular, cellular and integrative mechanisms regulating pulmonary vascular function in health and disease. In recent years, major advances have been gained in understanding the genetic and molecular basis of several pulmonary vascular diseases (i.e. pulmonary hypertension, pulmonary oedema formation), the role of mitochondria and cellular metabolism in controlling pulmonary vascular cell function, and the emerging effects of epigenetic regulation in the pulmonary circulation both in health and disease. This Special Issue includes several reviews covering these topics, as well as original research articles ranging from characterizing the functional relevance of TASK channel mutations to exploring the mechanism by which carbonic anhydrase attenuates hypoxic pulmonary vasoconstriction (HPV).

Precise regulation of lung barrier function, both endothelial and epithelial, is essential for proper gas exchange. Disruption of lung barrier function, and subsequent oedema formation, is a critical component of acute lung injury, with often fatal consequences. In this issue, Simmons et al. (2019) describe recent advances in uncovering the molecular mechanisms that cause, or promote recovery from, pulmonary endothelial barrier disruption and highlight promising targets for clinical trials.

Whether a consequence of lung injury/disruption of pulmonary barrier function, chronic lung disease or environmental factors (i.e. ascent to high altitude), hypoxia is a major stimulus for a variety of responses in the lung. As discussed by Eldridge & Wagner (2019), hypoxia is but one of many stimuli that can induce angiogenesis in the lung. Moreover, in contrast to the systemic circulation, where hypoxia induces vasodilatation, the pulmonary circulation uniquely contracts when oxygen levels fall. Both the mechanisms underlying the acute constrictor response to, and the long‐term consequences of, hypoxia have been intensely studied. With respect to mechanisms involved in oxygen sensing, Smith & Schumacker (2019) review recent results examining the role of mitochondria and reactive oxygen species in mediating HPV. A study by Pickerodt and colleagues (Pickerodt et al. 2019) demonstrates that while carbonic anhydrase can act as a nitrite reductase in vascular cells, exhaled nitric oxide levels were not altered by carbonic anhydrase during alveolar hypoxia, indicating that this is not the mechanism by which it inhibits HPV. With respect to chronic exposure to hypoxia, residence at high altitude is one of the most common causes of long‐term reduced alveolar oxygen levels. At high altitude, exercise capacity is limited and left ventricular filling and ejection are reduced. Work by Stembridge et al. (2019) in this issue explored the influenced of hypovolaemia on the decrease in left ventricular function. Interestingly, restoring left ventricular filling did not confer an improvement in maximal exercise performance. Chronic hypoxia due to high altitude can also exacerbate preexisting conditions. For example, Ferguson et al. (2019) present new evidence that in a mouse model, simulated life at altitude not only reduced exercise capacity, but also accelerated progression of sickle cell disease, adding to a growing list of factors that might increase risk of complications in patients.

Hypoxia was one of the first factors identified to cause pulmonary hypertension, yet the cellular mechanisms underlying this condition remain incompletely understood. Recent advances have identified several genes associated with increased risk for development of pulmonary hypertension. Cunningham et al. (2019) studied mutations in one such gene, KCNK3, which encodes TASK‐1 channels. They found that a mutation observed in patients substantially altered the functional properties of these channels, rendering the channels unresponsive to agonists. Unfortunately, growth in our knowledge of the underlying mechanisms and causes of pulmonary hypertension has not been matched by similar progress in treatment. Several factors contribute to this paradox, including lack of models that fully recapitulate human disease and research that has concentrated on initiation or early stages of disease rather than mechanisms maintaining the phenotype. Along these lines, there is increasing awareness of the differential phenotypes arising in various preclinical models. As an example, this issue features a Cross‐Talk debate (Vitali, 2019 and Penumatsa et al. 2019) regarding the suitability of the murine model of pulmonary arterial hypertension using the combined insults of vascular endothelial growth factor receptor inhibition and hypoxic exposure as a model for human disease. A review of the literature conducted by Hu et al. (2019) supports the hypothesis that failure of treatments to reverse pulmonary hypertension may be due to persistent activation of vascular cells resulting from epigenetic changes and aberrantly expressed genes in pulmonary vascular cells in later stage pulmonary hypertension, which may differ from the gene expression profile at early stage disease. Thus, understanding the temporal course of the disease, focusing on later stages and developing appropriate pre‐clinical models are likely to be needed to uncover new therapeutic targets.

It is becoming increasingly appreciated that pulmonary vascular disease is also a component of various other conditions. For example, Willson et al. (2019) describe recent literature demonstrating pulmonary vascular disease that develops in conjunction with metabolic syndrome. Similarly, Lai et al. (2019) discuss pulmonary vascular complications observed in the setting of heart failure with preserved ejection fraction. These reviews are complemented by an original research study performed in a novel, large animal model mimicking progression from isolated post‐capillary pulmonary hypertension secondary to left heart disease to combined pre‐ and post‐capillary pulmonary hypertension (van Duin et al. 2019). This transition is poorly understood, and data from this study demonstrated that inhibition of the endothelin pathway could potentially stop the progression of early stage post‐capillary disease.

Most studies exploring the effects of stimuli on pulmonary vascular responses have either focused on fetal/neonatal animals or adults. However, it is becoming apparent that insults experienced early in life not only have short‐term effects, but also can lead to long‐term consequences. For example, Sehgal et al. (2019) demonstrate that vascular abnormalities caused by intrauterine growth restriction leads to bronchopulmonary dysplasia. Moreover, Goss (2019) provides a review of recent findings showing that this type of perinatal insult, even if resolved as an infant, can lead to pulmonary vascular defects as an adult.

Finally, epigenetic phenomenon are increasingly recognized a regulators of gene and protein expression. As an example, in this issue, Perez‐Fransico et al. (Mondejar‐Parreno et al. 2019) describe a novel role for miRNAs (miR‐1) in regulating the expression of voltage‐gated K⁺ channels, in particular K_V1.5, shedding important light on a previously unknown regulatory pathway. This study is but one example of the ever increasing literature describing the roles of miRNAs, long non‐coding RNAs and other epigenetic alterations in a variety of cell functions. To begin to address this expanding field, Harvey & Chan (2019) describe novel bioinformatics approaches combining high‐throughput molecular data with computer simulations to provide unprecedented capabilities to integrate the copious amounts of genetic and proteomic data being generated in the field.

The collection of original research and review articles offered in this Special Issue represent topics that have not been highlighted as an integrated focus in a basic science journal. Our hope is that from this sample, readers will gain an appreciation for the diversity of work being performed with respect to the pulmonary vasculature, and authors will be tempted to consider The Journal of Physiology as a welcoming place for publishing their articles.

Additional information

Competing interests

None.

Funding

This work was supported by NIH grants HL073859 and HL126514.