Review Reports - Mechanisms Underlying Altitude-Induced and Group 3 Pulmonary Hypertension

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this review, the authors comprehensively discuss the molecular mechanisms linking hypoxia to pulmonary hypertension, emphasizing redox imbalance, PI3K–Akt signaling, Na⁺/H⁺ exchange, nitric oxide bioavailability, autophagy, mitochondrial dynamics, mitophagy, metabolic reprogramming, erythropoietin signaling, and inflammation.

The review primarily addresses changes in the intima (endothelial cells) and media (smooth muscle cells). However, it largely missed the important role of the adventitia and fibroblasts in the development of pulmonary hypertension (PH).

The adventitial layer is increasingly acknowledged as a key player in the initiation and spread of inflammation in PH. Existing studies show that the molecular maladaptations outlined in this review, such as mitochondrial dysfunction and ROS production, also induce an activated state in adventitial fibroblasts. This activation, in turn, helps attract immune cells into the pulmonary artery.

I recommend that the authors incorporate the listed maladaptations in fibroblasts into their discussion. In Section 3.9 (Inflammation), they should also address the crosstalk between stromal cells and various immune cells, explaining how this interaction promotes vascular remodeling.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript provides valuable information about the mechanisms underlying altitude-induced pulmonary hypertension (PH) pathogenesis, but requires expansion to achieve balance, updated references, and clearer integration of adaptive vs. pathological pathways to meet publication standards.

The title "Mechanisms underlying altitude and pathological pulmonary hypertension" is somewhat ambiguous. "Pathological" is vague and could be misinterpreted; consider revising to "Mechanisms Underlying Altitude-Induced and Group 3 Pulmonary Hypertension" to align more precisely with the content, which focuses on hypoxia-related PH, as per the WHO classifications in Table 1.
The abstract adequately summarizes key mechanisms but lacks specificity on therapeutic implications or potential targets (e.g., HIF-2α inhibitors). It should explicitly mention any novel insights or gaps in current knowledge to better highlight the contribution of this review manuscript.
The introduction provides a solid overview of PH prevalence and classifications, but underrepresents epidemiological data on altitude-induced PH in specific populations (e.g., Andean vs. Tibetan adaptations). Include more balanced global perspectives to avoid Eurocentric bias.
Table 1 correctly lists WHO groups, but the definition for Group 3 omits nuances like developmental lung diseases or hypoventilation syndromes. Expand the definitions of precision and cite the most recent WHO guidelines (e.g., 2022 updates, if applicable).
Figures 1 and 2 are useful schematics but lack sufficient labeling (e.g., specific interactions between HIF and AMPK are oversimplified). Add arrows with quantitative or directional details (activation/inhibition) and ensure color schemes are accessible for color-blind readers. For the convenience of the readers, please provide more information in the legend.
The discussion on HIF isoforms is strong, but the mitochondria subsection overemphasizes ROS without adequately addressing counter-regulatory mechanisms like SIRT1 or PGC-1α. This creates an imbalanced view of adaptive vs. maladaptive responses.
The lungs subsection cites conflicting roles of HIF-1α (protective in acute vs. pathological in chronic) but fails to reconcile these with recent meta-analyses. Similarly, the heart subsection is underdeveloped, with limited discussion on RV-specific adaptations; expand with data from human cohorts.
The claims by the authors about antioxidants' limited clinical translation are accurate but underexplored failed trials (e.g., N-acetylcysteine in PAH). Strengthen with a critical analysis of why preclinical success does not translate, including dosing or biomarker issues.
This section reviews known roles but misses integration with emerging crosstalk (e.g., PI3K-Akt and mTOR in metabolic reprogramming). Update with 2024-2025 studies on isoform-specific inhibitors to enhance relevance.
References appear dated, with many pre-2020 citations; incorporate references from 2023-2025 to reflect recent advances (e.g., single-cell RNA-seq in PH remodeling). Ensure all claims are supported, and avoid over-reliance on animal models without human validation.