Semaphorin Loss and Reduced FOXF1 Link BPD, PH

In a groundbreaking study published in Nature Communications, a team of researchers has unveiled critical insights into the molecular mechanisms underlying bronchopulmonary dysplasia (BPD) complicated by pulmonary hypertension (PH). This research sheds light on how disruptions in semaphorin signaling pathways and the consequential reduction in FOXF1 expression contribute to the pathological features of these devastating neonatal lung conditions, potentially opening new avenues for targeted therapies in preterm infants.

Bronchopulmonary dysplasia, a chronic lung disease primarily affecting premature infants who require prolonged oxygen therapy and mechanical ventilation, remains a significant clinical challenge due to its complex etiology and limited therapeutic options. When complicated by pulmonary hypertension, a condition characterized by increased blood pressure in the pulmonary arteries, the morbidity and mortality rates escalate sharply. Understanding the intricacies of the molecular crosstalk involved in this disease intersection has been a pressing unmet need in neonatal medicine.

The study by Shirazi and colleagues meticulously explores the role of semaphorin signaling—a family of proteins traditionally known for their functions in axon guidance during neural development—in vascular and pulmonary development. Remarkably, the researchers demonstrate that loss of semaphorin signaling is intricately linked to impaired lung vascularization and remodeling, hallmarks of bronchopulmonary dysplasia complicated by pulmonary hypertension. This pioneering investigation links semaphorin pathways to vascular pathology in the neonatal lung for the first time.

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Central to their findings is the functionally decreased expression of FOXF1, a transcription factor indispensable for mesenchymal-epithelial interactions during lung development. FOXF1’s downregulation appears to be not merely a marker but a driving force in the disease process. The authors present compelling evidence that diminished FOXF1 activity exacerbates vascular dysfunction, leading to the characteristic vascular rarefaction and heightened pulmonary pressures observed in BPD with PH. This concept establishes FOXF1 as a pivotal molecular node orchestrating lung structural integrity and vascular homeostasis.

The mechanistic dissection in this study reveals that semaphorin signaling loss leads to transcriptional repression of FOXF1, disrupting the genetic programs necessary for endothelial cell survival and proliferation. Endothelial cells, lining the interior surface of pulmonary vessels, are critical for maintaining vascular integrity and facilitating proper oxygen exchange. Their dysfunction results in hypoxia-induced vascular remodeling, a central pathophysiological event in neonatal pulmonary hypertension. The interdependence of semaphorin pathways and FOXF1 expression thus defines a novel pathogenic cascade in lung injury.

Utilizing advanced genetic models and high-resolution imaging techniques, the researchers delineated how attenuated semaphorin signals impair angiogenic cues, leading to defective capillary network formation. This vascular insufficiency not only compromises oxygen delivery but also contributes to persistent inflammation and fibrosis, hallmark features of bronchopulmonary dysplasia. The spatial and temporal expression patterns of FOXF1 were shown to precisely match regions of active vascular morphogenesis, highlighting its essential role in developmental lung biology.

Moreover, the investigators employed transcriptomic analyses to identify downstream targets and interacting partners of FOXF1 within the pulmonary vasculature. Their results suggest that FOXF1 modulates a broad array of genes involved in cell adhesion, migration, and extracellular matrix remodeling. This extensive regulatory network underscores the multifaceted influence of FOXF1 on lung tissue architecture, implicating its disruption in the widespread vascular and alveolar abnormalities seen in affected infants.

Importantly, this study transcends correlative observations by demonstrating causative links through gain- and loss-of-function experiments. Restoration of semaphorin signaling or FOXF1 expression in experimental models partially reversed vascular defects and improved pulmonary pressures, establishing a proof-of-concept for therapeutic intervention. These findings propose that modulating these molecular pathways could mitigate the progression of BPD with PH and improve long-term respiratory outcomes in survivors of preterm birth.

The translational relevance of these discoveries cannot be overstated. Current clinical management of BPD and associated pulmonary hypertension largely relies on supportive care and symptom management, with no approved pharmacological agents directly targeting the underlying molecular defects. This study’s identification of semaphorin-FOXF1 axis as a key determinant of vascular health introduces a potential biomolecular target for drug development, aiming to prevent or ameliorate lung injury early in its course.

From a broader scientific perspective, this work integrates developmental biology, vascular physiology, and molecular genetics to unravel complexities of neonatal lung disease. It exemplifies the power of multidisciplinary approaches—including genomics, cellular biology, and in vivo modeling—to address pressing pediatric health challenges. The insights gained here may also have implications for other pulmonary vascular diseases beyond infancy, such as adult pulmonary arterial hypertension and chronic obstructive pulmonary disease.

Clinically, the prospect of biomarker identification arises from these findings. Levels of FOXF1 expression or semaphorin activity could serve as indicators of disease severity or progression, guiding timely and individualized therapeutic strategies. Early detection of perturbations in these pathways may allow for interventions before irreversible lung damage occurs, changing the paradigm of neonatal intensive care.

The study also sparks questions regarding the interplay of genetic predisposition and environmental factors, such as oxygen toxicity and mechanical ventilation, in modulating semaphorin-FOXF1 signaling. Understanding how these external insults exacerbate molecular dysfunction will be crucial for designing comprehensive prevention measures, encompassing both molecular and clinical strategies.

Future research is undoubtedly needed to elucidate the precise molecular interactions and to translate these findings into clinically feasible treatments. The development of pharmacologic modulators or gene therapy vectors targeting the semaphorin-FOXF1 axis will require rigorous validation in preclinical models and eventually clinical trials, underscoring a promising but challenging translational pathway.

In conclusion, the insightful and methodically robust study by Shirazi et al. advances our molecular understanding of bronchopulmonary dysplasia complicated by pulmonary hypertension. By linking semaphorin signaling loss with FOXF1 downregulation, it underlines a novel pathogenic mechanism with far-reaching implications for diagnosis and therapy. This research not only adds a crucial piece to the puzzle of neonatal lung disease but also exemplifies the potential of targeted molecular medicine in transforming outcomes for vulnerable patient populations.

Subject of Research: Molecular mechanisms underlying bronchopulmonary dysplasia with pulmonary hypertension, focusing on semaphorin signaling and FOXF1 expression.

Article Title: Bronchopulmonary dysplasia with pulmonary hypertension associates with semaphorin signaling loss and functionally decreased FOXF1 expression.

Article References:
Shirazi, S.P., Negretti, N.M., Jetter, C.S. et al. Bronchopulmonary dysplasia with pulmonary hypertension associates with semaphorin signaling loss and functionally decreased FOXF1 expression. Nat Commun 16, 5004 (2025). https://doi.org/10.1038/s41467-025-60371-7

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Tags: bronchopulmonary dysplasia causeschronic lung disease in infantscomplications of pulmonary hypertensionFOXF1 expression in neonatesmolecular mechanisms of lung developmentneonatal lung disease mechanismsneonatal medicine researchpulmonary hypertension in preterm infantssemaphorin signaling pathwaystargeted therapies for BPDtherapeutic approaches for BPDvascular remodeling in BPD