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Publications

Researchers at computer

  • Mark Nicolls

    Stanford University Professor of Pulmonary and Critical Care Medicine

Publications

    • CES1 Deficiency is Associated With Metabolic Reprograming and Endothelial Dysfunction in Pulmonary Arterial Hypertension.

      Agarwal, S., Bankar, A., Heo, L., Mitra, A., Chakraborty, A., Liu, L., Huang, F., Swaminathan, G., Auer, N., Chelladurai, P., Guardado, E. S., Matos, J., Le, C., West, J., Suresh, K., Nair, R., Rabinovitch, M., Morisseau, C., Hammock, B. D., Wu, J., Arany, Z., Nicolls, M. R., De Jesus Perez, V.

      American journal of respiratory and critical care medicine

      ABSTRACT
      BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary microvascular loss and obliterative remodeling driven by endothelial dysfunction. Low penetrance of only BMPR2 mutations causing metabolic shifts in pulmonary microvascular endothelial cells (PMVECs), suggests role of additional genetic modifiers. Genetic screening of PAH PMVECs identified carboxylesterase1 (CES1)-an endoplasmic reticulum (ER) enzyme involved in lipid metabolism and detoxification-as a candidate regulator of endothelial metabolism and angiogenesis. We hypothesize that CES1 loss promotes endothelial dysfunction via metabolic reprogramming, lipotoxicity, and oxidative stress.METHODS: PAH/healthy PMVECs and lung tissues were obtained from transplant donors and commercial sources. CES1 knockdown and CES1 overexpression was performed in PMVECs for functional assays. Animal studies were done on CES1 heterozygous knockout (HET KO) and endothelial-specific knockout (ECKO) mice exposed to normoxia or hypoxia.RESULTS: CES1 expression was significantly reduced in PAH PMVECs and vascular lesions. CES1-deficient PMVECs exhibited increased apoptosis, reactive oxygen species (ROS) production, mitochondrial fragmentation, ER stress, and impaired angiogenesis. CES1 loss caused lipid droplet accumulation, reduced fatty acid oxidation, and glycolytic shift-phenotypes reversed by CES1 restoration. CES1 transcription was induced by BMPR2 via NRF2 activation, a key regulator of redox and metabolic homeostasis. CES1-deficient mice developed severe pulmonary hypertension (PH) under hypoxia, with extensive vascular remodeling, right ventricular dysfunction, and dysregulated angiogenesis and lipid metabolism pathways.CONCLUSIONS: CES1 is essential for pulmonary endothelial homeostasis and modifier of BMPR2 signaling. Restoring CES1 expression may serve as potential therapeutic strategy in reversing endothelial dysfunction and small-vessel loss.
      https://www.ncbi.nlm.nih.gov/pubmed/42085193 https://doi.org/10.1093/ajrccm/aamag077
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    • Power and sample-size estimation in human microbiome research.

      Zhou, Q., Lu, Y., Wang, L., Zhou, W., Oba, H., Zhou, Y., Shen, M., Qu, X., De Souza, C., Rayner, A., Chen, Y., Cheng, T. Y., Ling, Z., Li, L., Liu, C., Voigt, A. Y., Xiong, R., Oh, J., Spakowicz, D., Dravillas, C., Tian, A. W., Nicolls, M. R., Huynh, A. T., Chen, X., Hu, J., He, M., He, F., Snyder, M. P., Yang, J., Zhou, X.

      Med (New York, N.Y.)

      ABSTRACT
      Human microbiome research has become pivotal in advancing our understanding of complex diseases such as diabetes, inflammatory bowel disease, and cancer. Much of this work relies on comparing microbial communities across health and disease states, or case-control cohorts, using high-throughput metagenomic sequencing. Yet the very nature of sequencing-derived microbiome data makes robust cohort design and power-based sample-size estimation unusually difficult. Unlike other omics, microbiome profiles are compositional, sparse, and often zero inflated, properties that complicate statistical modeling and inflate sample-size requirements. These challenges are further compounded by the diversity of analytical frameworks-ranging from diversity indices to causal inference-each built on different statistical assumptions and optimized for a distinct research hypothesis. This review synthesizes current approaches around the study design and sample-size estimation in microbiome research, aiming to provide clinicians and researchers with practical guidance for navigating the statistical complexities unique to this field.
      https://www.ncbi.nlm.nih.gov/pubmed/42302785 https://doi.org/10.1016/j.medj.2026.101174
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    • Nanomedicine in Lung Transplantation: Emerging Solutions for Clinical Challenges.

      Maskos, A., Krishnan, A., Duda, M. M., Aranda-Michel, E., Heng, E. E., Berg, A., Alnasir, D., Hildinger, J., Iske, J., Michel, S., Forouharshad, M., Nicolls, M. R., Parikh, K. S., MacArthur, J. W.

      American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

      ABSTRACT
      Lung transplantation (LT) remains the definitive treatment for select patients with end-stage respiratory failure. Despite refinements in donor selection, organ preservation, and perioperative management, LT is still associated with the shortest median survival among all solid organ transplants. Major clinical bottlenecks include airway complications (AC), ischemia-reperfusion injury (IRI), organ rejection and chronic lung allograft dysfunction (CLAD), and suboptimal donor organ quality. Current management is constrained by delayed diagnosis, anatomical delivery barriers, and the off-target toxicities of conventional systemic drug delivery. Nanomedicine, the medical application of nanoscale materials and devices, offers several distinct opportunities in LT: non-invasive detection and imaging of graft injury, protection of unstable cargo, context-specific controlled drug release, and cell-specific targeting. However, clinical translation is still in its early stages, with only liposomal cyclosporine having advanced to phase III clinical trials; most alternative platforms remain preclinical. Here, we categorize the classes of nanomedicines and their specific delivery routes in LT, mapping these technologies onto clinical bottlenecks and critically appraising each platform to frame a path toward clinical translation.
      https://www.ncbi.nlm.nih.gov/pubmed/42744050 https://doi.org/10.1016/j.ajt.2026.09.013
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    • Cd74-Vegfr3 Signaling Drives Lymphatic Remodeling in Hypoxia-Induced Pulmonary Hypertension

      Moss, M., Klouda, T., Li, Y., Liu, Y., Kim, Y., Tian, W., Nicolls, M. R., Wu, J., Chen, H., Lee, E., Tran-Lundmark, K., Yuan, K.

      https://doi.org/10.1093/ajrccm/aamag162.5885
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    • Hypoxia Induces Adaptive Lymphangiogenesis via Cd74 and Vegfr3 to Modulate Pulmonary Hypertension.

      Moss, M. E., Klouda, T., Li, Y., Liu, Y., Tan, M., Kim, Y., Hao, Y., Tian, W., Nicolls, M. R., Wu, J. C., Bucala, R., Chen, H., Lee, E., Tran-Lundmark, K., Raby, B., Yuan, K.

      Circulation research

      ABSTRACT
      Pulmonary arterial hypertension (PAH) is characterized by excessive remodeling of the proximal and distal arterioles, driven by endothelial cell apoptosis and uncontrolled mural cell proliferation. Increasing evidence suggests an important role of inflammation in PAH, but 1 crucial part of the immune system, the pulmonary lymphatics, has been largely overlooked. Patients with idiopathic PAH often develop abnormal tertiary lymphoid structures adjacent to remodeled arteries, yet the role of lymphatic vessels in PAH pathogenesis and vascular remodeling remains unclear. Using a mouse model to specifically label lymphatic endothelial cells (Prox1-CreERT2::Rosa26-LSL-tdT), we found that pulmonary lymphatic vessels proliferated and dilated in response to hypoxia. We further showed that Vegfr3 inhibition using MAZ51 reduced hypoxia induced lymphangiogenesis and was associated with severe pulmonary hypertension. Additionally, lymphatic endothelial cell-specific deletion of Vegfr3 (Prox1-CreERT2::Vegfr3fl/fl) prevents adaptive lymphangiogenesis and exacerbates pulmonary hypertension, resulting in right ventricular hypertrophy. Comparative single-cell RNA sequencing analysis of human idiopathic PAH and hypoxia-induced pulmonary hypertension mouse lungs revealed upregulation of CD74/Cd74 in lymphatic endothelial cell clusters, and in humans this was associated with enhanced expression of FLT4/VEGFR3 and downstream mediators in the MEK/ERK signaling pathway. Consistently, increased CD74 expression was observed in lymphatic vessels in human idiopathic PAH lung sections, and CD74 overexpression in human lymphatic cells was associated with impaired barrier permeability and coexpression of VEGFR3. Together, these findings provide novel insights into the role of lymphatic Cd74/CD74 activation in pulmonary hypertension development and suggest that therapies aimed at augmenting lymphatic function may improve outcomes in patients with PAH.
      https://www.ncbi.nlm.nih.gov/pubmed/42233213 https://doi.org/10.1161/CIRCRESAHA.126.326822
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    • Altered baseline immunological state and impaired immune response to SARS-CoV-2 mRNA vaccination in lung transplant recipients.

      Hu, M., Oliveira, A. P., Fang, Z., Feng, Y., Miranda, M., Kowli, S., Arunachalam, P. S., Vasudevan, G., Hui, H. S., Grifoni, A., Sette, A., Litvack, M., Rouphael, N., Suthar, M. S., Ji, X., Maecker, H. T., Hagan, T., Dhillon, G., Nicolls, M. R., Pulendran, B.

      Cell reports. Medicine

      ABSTRACT
      The effectiveness of COVID-19 mRNA vaccines is diminished in organ transplant patients. Using a multi-omics approach, we investigate the immunological state of lung transplant (LTX) recipients at baseline and after SARS-CoV-2 mRNA vaccination compared to healthy controls (HCs). LTX patients exhibit a baseline immune profile resembling severe COVID-19 and sepsis, characterized by elevated pro-inflammatory cytokines (e.g., EN-RAGE [also known as S100A12], interleukin [IL]-6), reduced human leukocyte antigen (HLA)-DR expression on monocytes and dendritic cells, impaired cytokine production, and increased plasma microbial products. Single-cell RNA sequencing identifies an enriched monocyte cluster in LTX patients marked by high S100A family expression and reduced cytokine and antigen presentation genes. Post vaccination, LTX patients show diminished antibody, B cell, and T cell responses, along with blunted innate immune signatures. Integrative analysis links these altered baseline immunological features to impaired vaccine responses. These findings provide critical insights into the immunosuppressed condition of LTX recipients and their reduced vaccine-induced adaptive and innate immune responses.
      https://www.ncbi.nlm.nih.gov/pubmed/40187358 https://doi.org/10.1016/j.xcrm.2025.102050
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    • Microbiome-Immune Interaction in Pulmonary Arterial Hypertension: What Have We Missed?

      Zhou, X., Tian, W., Gu, S., Rabinovitch, M., Nicolls, M. R., Snyder, M. P.

      Research (Washington, D.C.)

      ABSTRACT
      Pulmonary arterial hypertension (PAH) is a devastating disease characterized by perivascular inflammation, immune dysregulation, and vascular remodeling. Recent studies have unveiled a potential link between the gut microbiome and PAH pathogenesis, suggesting that microbial dysbiosis and increased intestinal permeability may contribute to the inflammatory pathology in PAH and ultimately disease progression. This perspective highlights the emerging evidence of the role of leaky gut in PAH, the interplay between microbiota-induced immune responses, and the activation of endogenous retroviruses like human endogenous retrovirus K. Understanding these complex interactions opens new interdisciplinary avenues for research and therapeutic interventions, potentially transforming PAH management through microbiome-targeted strategies.
      https://www.ncbi.nlm.nih.gov/pubmed/40207016 https://doi.org/10.34133/research.0669
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    • A Cross-Species and Sex-Specific Meta-Analysis of Transcriptomic Studies of Pulmonary Hypertension.

      Zhao, L., Cunningham, C. M., Hong, J., Agarwal, S., Yuan, K., de Jesus Perez, V. A., Nicolls, M. R.

      American journal of respiratory cell and molecular biology

      ABSTRACT
      Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling and right ventricle (RV) dysfunction. Among the five PH groups, group 1 pulmonary arterial hypertension (PAH) is a particularly serious condition characterized by a poor prognosis. PAH can be in idiopathic (IPAH), associated (APAH), and heritable (HPAH) forms, and has a notable female predominance. A number of in vivo PH models in rodents together with in vitro cultured vascular cells such as pulmonary arterial endothelial cells (PAECs) and pulmonary arterial smooth muscle cells (PASMCs) derived from PAH patients have been widely used to reproduce the pathological disease features. To systematically evaluate the in vivo and in vitro efficacy of the existing PH model systems, publicly available whole transcriptome data from both humans and rodents were collected and analyzed. Subgroups of Schistosoma-induced female PH in mice and male chronic hypoxia (CH)-PH model in rats correlated well with human HPAH and IPAH lungs, respectively. A SU5416-CH (SuHx) PH model is well connected to the decompensated RVs of human PAH. Sex dimorphisms have been observed in PAH derived PAECs and PASMCs, independent of gonadal hormones. We conducted, for the first time, a meta-cohort and cross-species comparative study and identified optimal in vivo and in vitro PH model systems that recapitulate certain aspects of the human PH, which could provide novel insights into new therapeutic avenues in PH.
      https://www.ncbi.nlm.nih.gov/pubmed/39928415 https://doi.org/10.1165/rcmb.2024-0410OC
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    • B cells in pulmonary arterial hypertension: friend, foe or bystander?

      Sanges, S., Tian, W., Dubucquoi, S., Chang, J. L., Collet, A., Launay, D., Nicolls, M. R.

      The European respiratory journal

      ABSTRACT
      There is an unmet need for new therapeutic strategies that target alternative pathways to improve the prognosis of patients with pulmonary arterial hypertension (PAH). As immunity has been involved in the development and progression of vascular lesions in PAH, we review the potential contribution of B cells in its pathogenesis and evaluate the relevance of B cell-targeted therapies. Circulating B cell homeostasis is altered in PAH patients, with total B-cell lymphopenia, abnormal subset distribution (expansion of naive and antibody-secreting cells, reduction of memory B cells) and chronic activation. B cells are recruited to the lungs through local chemokine secretion, and activated by several mechanisms: 1) interaction with lung vascular auto-antigens through cognate B cell receptors; 2) co-stimulatory signals provided by T follicular helper (Tfh) cells (IL-21), T helper 2 (Th2) cells and mast cells (IL-4, IL-6 and IL-13); and 3) increased survival signals provided by B cell activating factor (BAFF) pathways. This activity results in the formation of germinal centres within perivascular tertiary lymphoid organs and in the local production of pathogenic autoantibodies that target the pulmonary vasculature and vascular stabilization factors (including angiotensin-II/endothelin-1 receptors and bone morphogenetic protein receptors). B cells also mediate their effects through enhanced production of pro-inflammatory cytokines, reduced anti-inflammatory properties by regulatory B cells, IgG-induced complement activation, and IgE-induced mast cell activation. Precision-medicine approaches targeting B cell immunity are a promising direction for select PAH conditions, as suggested by the efficacy of anti-CD20 therapy in experimental models and a trial of rituximab in systemic sclerosis-associated PAH.
      https://www.ncbi.nlm.nih.gov/pubmed/38485150 https://doi.org/10.1183/13993003.01949-2023
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    • VIEWING PULMONARY HYPERTENSION THROUGH A PEDIATRIC LENS.

      Agarwal, S., Fineman, J., Cornfield, D. N., Alvira, C. M., Zamanian, R. T., Goss, K., Yuan, K., Bonnet, S., Boucherat, O., Pullamsetti, S., Alcázar, M. A., Goncharova, E., Kudryashova, T. V., Nicolls, M. R., de Jesús Pérez, V.

      The European respiratory journal

      https://www.ncbi.nlm.nih.gov/pubmed/38575157 https://doi.org/10.1183/13993003.01518-2023
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    • HIF2A Activation Reduces Pulmonary Angiogenesis and Promotes Vascular Remodeling in PAH by Suppressing Wnt7a Production in Pulmonary Endothelial Cells

      Mitra, A., Yi, D., Agarwal, S., Tian, A., Jiang, X., Nicolls, M. R., Zhiyu, D., Perez, V.

    • Editorial: Regulatory T cells in immune-mediated diseases.

      Tran, G. T., Verma, N. D., Nicolls, M. R., Hall, B. M.

      Frontiers in immunology

      https://www.ncbi.nlm.nih.gov/pubmed/39763678 https://doi.org/10.3389/fimmu.2024.1537314
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    • CES1 Deficiency Is Associated With Endothelial Dysfunction and Metabolic Reprograming in PAH

      Agarwal, S., Heo, L., Chakraborty, A., West, J. D., Suresh, K., Nair, R. V., Nicolls, M. R., Morisseau, C., Hammock, B. D., Lafyatis, R. A., Kawut, S. M., Zamanian, R. T., Perez, V.

    • Pericytes contribute to pulmonary vascular remodeling via HIF2α signaling.

      Kim, H., Liu, Y., Kim, J., Kim, Y., Klouda, T., Fisch, S., Baek, S. H., Liu, T., Dahlberg, S., Hu, C. J., Tian, W., Jiang, X., Kosmas, K., Christou, H. A., Korman, B. D., Vargas, S. O., Wu, J. C., Stenmark, K. R., Perez, V. d., Nicolls, M. R., Raby, B. A., Yuan, K.

      EMBO reports

      ABSTRACT
      Vascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world's most afflicted cardiovascular conditions, including pulmonary arterial hypertension (PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells (SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here, we report that hypoxia-inducible factor 2α (HIF2α) expression is increased in the lung tissues of PAH patients, and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension (PH) models, we show that HIF2α is a major molecular regulator for the transformation of pericytes into SMC-like cells. Pericyte-selective HIF2α overexpression in mice exacerbates PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the crucial role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH.
      https://www.ncbi.nlm.nih.gov/pubmed/38243138 https://doi.org/10.1038/s44319-023-00054-w
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    • Rat microbial biogeography and age-dependent lactic acid bacteria in healthy lungs.

      Zhao, L., Cunningham, C. M., Andruska, A. M., Schimmel, K., Ali, M. K., Kim, D., Gu, S., Chang, J. L., Spiekerkoetter, E., Nicolls, M. R.

      Lab animal

      ABSTRACT
      The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined the multitissue microbial biogeography of healthy Fischer 344 rats across their lifespan. Microbial community profiling data were extracted and integrated with host transcriptomic data from the Sequencing Quality Control consortium. Unsupervised machine learning, correlation, taxonomic diversity and abundance analyses were performed to determine and characterize the rat microbial biogeography and identify four intertissue microbial heterogeneity patterns (P1-P4). We found that the 11 body habitats harbored a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundance progressively declined in lungs from breastfed newborn to adolescence/adult, and was below detectable levels in elderly rats. Bioinformatics analyses indicate that the abundance of LAB may be modulated by the lung-immune axis. The presence and levels of LAB in lungs were further evaluated by PCR in two validation datasets. The lung, testes, thymus, kidney, adrenal and muscle niches were found to have age-dependent alterations in microbial abundance. The 357 microbial signatures were positively correlated with host genes in cell proliferation (P1), DNA damage repair (P2) and DNA transcription (P3). Our study established a link between the metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures could be useful for microbiome therapeutic approaches to human health and life quality enhancement.
      https://www.ncbi.nlm.nih.gov/pubmed/38297075 https://doi.org/10.1038/s41684-023-01322-x
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    • Ultrasound Neuromodulation of an Anti-Inflammatory Pathway at the Spleen Improves Experimental Pulmonary Hypertension.

      Zafeiropoulos, S., Ahmed, U., Bekiaridou, A., Jayaprakash, N., Mughrabi, I. T., Saleknezhad, N., Chadwick, C., Daytz, A., Kurata-Sato, I., Atish-Fregoso, Y., Carroll, K., Al-Abed, Y., Fudim, M., Puleo, C., Giannakoulas, G., Nicolls, M., Diamond, B., Zanos, S.

      Circulation research

      ABSTRACT
      Inflammation is pathogenically implicated in pulmonary arterial hypertension; however, it has not been adequately targeted therapeutically. We investigated whether neuromodulation of an anti-inflammatory neuroimmune pathway involving the splenic nerve using noninvasive, focused ultrasound stimulation of the spleen (sFUS) can improve experimental pulmonary hypertension.Pulmonary hypertension was induced in rats either by Sugen 5416 (20 mg/kg SQ) injection, followed by 21 (or 35) days of hypoxia (sugen/hypoxia model), or by monocrotaline (60 mg/kg IP) injection (monocrotaline model). Animals were randomized to receive either 12-minute-long sessions of sFUS daily or sham stimulation for 14 days. Catheterizations, echocardiography, indices of autonomic function, lung and heart histology and immunohistochemistry, spleen flow cytometry, and lung single-cell RNA sequencing were performed after treatment to assess the effects of sFUS.Splenic denervation right before induction of pulmonary hypertension results in a more severe disease phenotype. In both sugen/hypoxia and monocrotaline models, sFUS treatment reduces right ventricular systolic pressure by 25% to 30% compared with sham treatment, without affecting systemic pressure, and improves right ventricular function and autonomic indices. sFUS reduces wall thickness, apoptosis, and proliferation in small pulmonary arterioles, suppresses CD3+ and CD68+ cell infiltration in lungs and right ventricular fibrosis and hypertrophy and lowers BNP (brain natriuretic peptide). Beneficial effects persist for weeks after sFUS discontinuation and are more robust with early and longer treatment. Splenic denervation abolishes sFUS therapeutic benefits. sFUS partially normalizes CD68+ and CD8+ T-cell counts in the spleen and downregulates several inflammatory genes and pathways in nonclassical and classical monocytes and macrophages in the lung. Differentially expressed genes in those cell types are significantly enriched for human pulmonary arterial hypertension-associated genes.sFUS causes dose-dependent, sustained improvement of hemodynamic, autonomic, laboratory, and pathological manifestations in 2 models of experimental pulmonary hypertension. Mechanistically, sFUS normalizes immune cell populations in the spleen and downregulates inflammatory genes and pathways in the lung, many of which are relevant in human disease.
      https://www.ncbi.nlm.nih.gov/pubmed/38712557 https://doi.org/10.1161/CIRCRESAHA.123.323679
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    • 3D Imaging Reveals Complex Microvascular Remodeling in the Right Ventricle in Pulmonary Hypertension.

      Ichimura, K., Boehm, M., Andruska, A. M., Zhang, F., Schimmel, K., Bonham, S., Kabiri, A., Kheyfets, V. O., Ichimura, S., Reddy, S., Mao, Y., Zhang, T., Wang, G., Santana, E. J., Tian, X., Essafri, I., Vinh, R., Tian, W., Nicolls, M. R., Yajima, S., Shudo, Y., MacArthur, J. W., Woo, Y. J., Metzger, R. J., Spiekerkoetter, E.

      Circulation research

      ABSTRACT
      Pathogenic concepts of right ventricular (RV) failure in pulmonary arterial hypertension focus on a critical loss of microvasculature. However, the methods underpinning prior studies did not take into account the 3-dimensional (3D) aspects of cardiac tissue, making accurate quantification difficult. We applied deep-tissue imaging to the pressure-overloaded RV to uncover the 3D properties of the microvascular network and determine whether deficient microvascular adaptation contributes to RV failure.Heart sections measuring 250-µm-thick were obtained from mice after pulmonary artery banding (PAB) or debanding PAB surgery and properties of the RV microvascular network were assessed using 3D imaging and quantification. Human heart tissues harvested at the time of transplantation from pulmonary arterial hypertension cases were compared with tissues from control cases with normal RV function.Longitudinal 3D assessment of PAB mouse hearts uncovered complex microvascular remodeling characterized by tortuous, shorter, thicker, highly branched vessels, and overall preserved microvascular density. This remodeling process was reversible in debanding PAB mice in which the RV function recovers over time. The remodeled microvasculature tightly wrapped around the hypertrophied cardiomyocytes to maintain a stable contact surface to cardiomyocytes as an adaptation to RV pressure overload, even in end-stage RV failure. However, microvasculature-cardiomyocyte contact was impaired in areas with interstitial fibrosis where cardiomyocytes displayed signs of hypoxia. Similar to PAB animals, microvascular density in the RV was preserved in patients with end-stage pulmonary arterial hypertension, and microvascular architectural changes appeared to vary by etiology, with patients with pulmonary veno-occlusive disease displaying a lack of microvascular complexity with uniformly short segments.3D deep tissue imaging of the failing RV in PAB mice, pulmonary hypertension rats, and patients with pulmonary arterial hypertension reveals complex microvascular changes to preserve the microvascular density and maintain a stable microvascular-cardiomyocyte contact. Our studies provide a novel framework to understand microvascular adaptation in the pressure-overloaded RV that focuses on cell-cell interaction and goes beyond the concept of capillary rarefaction.
      https://www.ncbi.nlm.nih.gov/pubmed/38770652 https://doi.org/10.1161/CIRCRESAHA.123.323546
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    • CT strain metrics allow for earlier diagnosis of bronchiolitis obliterans syndrome after hematopoietic cell transplant.

      Sharifi, H., Bertini, C. D., Alkhunaizi, M., Hernandez, M. P., Musa, Z., Borges, C., Turk, I., Bashoura, L., Dickey, B. F., Cheng, G. S., Yanik, G. A., Galban, C., Guo, H. H., Godoy, M., Reinhardt, J., Hoffman, E., Castro, M., Rondon, G., Alousi, A., Champlin, R. E., Shpall, E. J., Lu, Y., Peterson, S. W., Datta, K., Nicolls, M., Hsu, J. L., Sheshadri, A.

      Blood advances

      ABSTRACT
      Bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation (HCT) is associated with substantial morbidity and mortality. Quantitative CT (qCT) can help diagnose advanced BOS meeting National Institutes of Health (NIH) criteria (NIH-BOS) but has not been used to diagnose early, often asymptomatic BOS (early BOS), limiting the potential for early intervention and improved outcomes. Using Pulmonary Function Tests (PFT) to define NIH-BOS, early BOS, and mixed BOS (NIH-BOS with restrictive lung disease) in patients from two large cancer centers, we applied qCT to identify early BOS and distinguish between types of BOS. Patients with transient impairment or healthy lungs were included for comparison. PFT were done at month 0, 6, and 12. Analysis was performed with association statistics, principal component analysis, conditional inference trees (CIT), and machine learning (ML) classifier models. Our cohort included 84 allogeneic HCT recipients -- 66 BOS (NIH-defined, early, or mixed) and 18 without BOS. All qCT metrics had moderate correlation with Forced Expiratory Volume in 1 second, and each qCT metric differentiated BOS from those without BOS (non-BOS) (P < 0.0001). CIT's distinguished 94% of participants with BOS versus non-BOS, 85% early BOS versus non-BOS, 92% early BOS versus NIH-BOS. ML models diagnosed BOS with area under the curve (AUC) 0.84 (95% confidence interval [CI] 0.74-0.94) and early BOS with AUC 0.84 (95% CI 0.69 - 0.97). Quantitative CT metrics can identify individuals with early BOS, paving the way for closer monitoring and earlier treatment in this vulnerable population.
      https://www.ncbi.nlm.nih.gov/pubmed/39163616 https://doi.org/10.1182/bloodadvances.2024013748
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    • PTPN1 Deficiency Modulates BMPR2 Signaling and Induces Endothelial Dysfunction in Pulmonary Arterial Hypertension.

      Ali, M. K., Tian, X., Zhao, L., Schimmel, K., Rhodes, C. J., Wilkins, M. R., Nicolls, M. R., Spiekerkoetter, E. F.

      Cells

      ABSTRACT
      Bone morphogenic protein receptor 2 (BMPR2) expression and signaling are impaired in pulmonary arterial hypertension (PAH). How BMPR2 signaling is decreased in PAH is poorly understood. Protein tyrosine phosphatases (PTPs) play important roles in vascular remodeling in PAH. To identify whether PTPs modify BMPR2 signaling, we used a siRNA-mediated high-throughput screening of 22,124 murine genes in mouse myoblastoma reporter cells using ID1 expression as readout for BMPR2 signaling. We further experimentally validated the top hit, PTPN1 (PTP1B), in healthy human pulmonary arterial endothelial cells (PAECs) either silenced by siRNA or exposed to hypoxia and confirmed its relevance to PAH by measuring PTPN1 levels in blood and PAECs collected from PAH patients. We identified PTPN1 as a novel regulator of BMPR2 signaling in PAECs, which is downregulated in the blood of PAH patients, and documented that downregulation of PTPN1 is linked to endothelial dysfunction in PAECs. These findings point to a potential involvement for PTPN1 in PAH and will aid in our understanding of the molecular mechanisms involved in the disease.
      https://www.ncbi.nlm.nih.gov/pubmed/36672250 https://doi.org/10.3390/cells12020316
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    • Decreasing ELK3 expression improves Bone Morphogenetic Protein Receptor 2 signaling and pulmonary vascular cell function in PAH.

      Ali, M. K., Zhao, L., Perez, V. d., Nicolls, M. R., Spiekerkoetter, E. F.

      bioRxiv : the preprint server for biology

      ABSTRACT
      ELK3 is upregulated in blood and pulmonary vascular cells of PAH patients and may play a significant role in PAH potentially through modulating BMPR2 signaling.
      https://www.ncbi.nlm.nih.gov/pubmed/36711443 https://doi.org/10.1101/2023.01.14.524023
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