Reply to Schulze and Musch.

Letter to the EditorReply to Schulze and MuschGary Marshall Long, Andrew R. Coggan, and Mary Beth BrownGary Marshall LongKinesiology, Health and Sport Sciences, University of Indianapolis, Indianapolis, Indiana, United States, Andrew R. CogganDepartment of Kinesiology, Indiana University, Purdue University Indianapolis, Indianapolis, Indiana, United States, and Mary Beth BrownDepartment of Rehabilitation Medicine, University of Washington School of Medicine, Seattle, Washington, United StatesPublished Online:19 Jul 2023https://doi.org/10.1152/ajpregu.00151.2023MoreSectionsPDF (193 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat reply: We thank Schulze and Musch for their considered letter regarding our manuscript entitled “Skeletal muscle blood flow during exercise is reduced in a rat model of pulmonary hypertension” (1). We wholeheartedly agree with the contention that scientific study in pulmonary arterial hypertension (PAH) has failed to adequately represent females in both animal modeling and patient populations. This is despite the approximate two- to fourfold increase in prevalence of the disease in females (2, 3) to which the authors have importantly alluded. Indeed, our group and collaborators have sought to investigate the sex differences in PAH from a mechanistic perspective, including its impact on exercise intolerance as a consequence of the disease (4–6). We feel this work is critical in understanding the complex pathophysiology underpinning sex disparities seen in patients and advocate strongly for continued work in this area. Indeed, we identify this as an important limitation in the manuscript in question and encourage future work to address this issue as a matter of urgency.We note that although the monocrotaline (MCT) model of pulmonary hypertension has been used for decades, it has limitations (7), including a disease process that may not effectively mimic PAH in humans and a dose dependency that leads to variable hemodynamic changes over time. In addition, MCT has been shown to produce a less-severe model of the disease in females (8). Although this should not discourage the use of MCT in female rats, it has important implications for our study. First, we intended to study exercise responses in a reliably severe phenotype, hence our use of the higher 60 mg/kg MCT dose, previously shown to induce a decompensated heart failure (9). The potentially attenuated MCT response in the female rat was therefore considered a methodological challenge in this case. Second, our primary end point (skeletal muscle blood flow) was a technically challenging, highly invasive procedure that had not yet been carried out in a decompensated PAH model. To minimize animal numbers while maintaining a reliably severe model, we chose to limit the study to male rats. Despite these considerations, it is not our intention to discourage further exploration of the effects of MCT in the female rat. Instead, we identified a potential difference in severity of PAH development that was integral to the nature of this study and sought to recognize it as a potential limitation. We genuinely welcome further study of the MCT model in males and female rats and see value in continued work on the important sex differences present in the disease. We appreciate the thorough consideration of this issue as presented by Schulze and Musch and welcome further attention on this critical aspect of PAH research.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.REFERENCES1. Long GM, Troutman AD, Gray DA, Fisher AJ, Lahm T, Coggan AR, Brown MB. Skeletal muscle blood flow during exercise is reduced in a rat model of pulmonary hypertension. Am J Physiol Regul Integr Comp Physiol 323: R561–R570, 2022. doi:10.1152/ajpregu.00327.2021. Link | ISI | Google Scholar2. Mair KM, Johansen AK, Wright AF, Wallace E, MacLean MR. Pulmonary arterial hypertension: basis of sex differences in incidence and treatment response. Br J Pharmacol 171: 567–579, 2014. doi:10.1111/bph.12281. Crossref | PubMed | ISI | Google Scholar3. Batton KA, Austin CO, Bruno KA, Burger CD, Shapiro BP, Fairweather D. Sex differences in pulmonary arterial hypertension: role of infection and autoimmunity in the pathogenesis of disease. Biol Sex Differ 9: 15, 2018. doi:10.1186/s13293-018-0176-8. Crossref | PubMed | ISI | Google Scholar4. Frump AL, Goss KN, Vayl A, Albrecht M, Fisher A, Tursunova R, Fierst J, Whitson J, Cucci AR, Brown MB, Lahm T. Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones. Am J Physiol Lung Cell Mol Physiol 308: L873–L890, 2015. doi:10.1152/ajplung.00006.2015. Link | ISI | Google Scholar5. Lahm T, Albrecht M, Fisher AJ, Selej M, Patel NG, Brown JA, Justice MJ, Brown MB, Van Demark M, Trulock KM, Dieudonne D, Reddy JG, Presson RG, Petrache I. 17β-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated effects. Am J Respir Crit Care Med 185: 965–980, 2012. doi:10.1164/rccm.201107-1293OC. Crossref | PubMed | ISI | Google Scholar6. Lahm T, Tuder RM, Petrache I. Progress in solving the sex hormone paradox in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 307: L7–L26, 2014. doi:10.1152/ajplung.00337.2013. Link | ISI | Google Scholar7. Gomez-Arroyo JG, Farkas L, Alhussaini AA, Farkas D, Kraskauskas D, Voelkel NF, Bogaard HJ. The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol 302: L363–L369, 2012. doi:10.1152/ajplung.00212.2011. Link | ISI | Google Scholar8. Bal E, Ilgin S, Atli O, Ergun B, Sirmagul B. The effects of gender difference on monocrotaline-induced pulmonary hypertension in rats. Hum Exp Toxicol 32: 766–774, 2013. doi:10.1177/0960327113477874. Crossref | PubMed | ISI | Google Scholar9. Schermuly RT, Kreisselmeier KP, Ghofrani HA, Yilmaz H, Butrous G, Ermert L, Ermert M, Weissmann N, Rose F, Guenther A, Walmrath D, Seeger W, Grimminger F. Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats. Am J Respir Crit Care Med 169: 39–45, 2004. doi:10.1164/rccm.200302-282OC. Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESCorrespondence: M. B. Brown (mbbrown1@uw.edu). Download PDF Previous Back to Top FiguresReferencesRelatedInformation Related ArticlesSkeletal muscle blood flow during exercise is reduced in a rat model of pulmonary hypertension 31 May 2023American Journal of Physiology-Regulatory, Integrative and Comparative Physiology More from this issue > Volume 325Issue 2August 2023Pages R227-R227 Crossmark Copyright & PermissionsCopyright © 2023 the American Physiological Society.https://doi.org/10.1152/ajpregu.00151.2023PubMed37467442History Received 21 June 2023 Accepted 21 June 2023 Published online 19 July 2023 Published in print 1 August 2023 Metrics