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Article

Mitochondrial Transplantation from Bone Marrow Mesenchymal Stromal Cells Combined with Sildenafil Attenuated Vascular Remodeling and Improved Right Ventricular Dysfunction in Experimental Pulmonary Arterial Hypertension

by
Maria E. de S. F. Onofre
1,
Renata T. Santos
1,
Nazareth de N. Rocha
1,2,
Dayene de A. F. Caldeira
1,
Johnatas D. Silva
1,*,
Carla M. da Silva
1,
Monique M. Melo
1,
Mayck M. A. da Silva
1,
Clara R. S. Pastor
1,
Julia D. Batista
1,
Isadora A. Botelho
1,
Rodrigo G. Veras
1,
Sabrina S. de S. Serra
1,
Julianna D. Zeidler
1,
Patricia R. M. Rocco
1,
Fernanda F. Cruz
1 and
Pedro L. Silva
1,*
1
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
2
Instituto Biomedico, Universidade Federal Fluminense, Niterói 24120-130, RJ, Brazil
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(4), 1761; https://doi.org/10.3390/ijms27041761
Submission received: 16 January 2026 / Revised: 10 February 2026 / Accepted: 10 February 2026 / Published: 12 February 2026
(This article belongs to the Special Issue Advances in Lung Research: From Mechanisms to Therapeutic Innovation)
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Abstract

Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling and right ventricular (RV) dysfunction, processes that are increasingly associated with disturbances in cellular metabolism. We investigated whether transplantation of exogenous mitochondria derived from bone marrow mesenchymal stromal cells, alone or combined with sildenafil, could improve mitochondrial homeostasis and attenuate cardiopulmonary remodeling in monocrotaline-induced PAH. Male Wistar rats were assigned to control (CTRL, n = 8) or PAH (n = 32) groups. Fourteen days after induction of PAH, animals were randomized to receive saline, sildenafil (20 mg/kg/day for 14 days), intravenous mitochondrial transplantation (100 μg, days 14 and 21), or combined therapy. On day 28, echocardiography, invasive measurement of RV systolic pressure (RVSP), pulmonary vascular histology, gene expression analyses (vimentin, VE-cadherin, and mitochondrial metabolism–related genes), and high-resolution respirometry were performed. All treatments significantly reduced RVSP compared with untreated PAH. Mitochondrial therapy, alone or combined with sildenafil, decreased arteriolar α-smooth muscle actin content, whereas endothelial–mesenchymal transition was attenuated only with combined treatment. Mitochondrial transplantation and sildenafil increased Complex I–dependent respiration, whereas Complex IV activity improved exclusively with mitochondrial therapy. Combined treatment reduced plasma IL-6 and IL-1β levels compared with PAH. Thus, mitochondrial transplantation, particularly when combined with sildenafil, improved RV function, limited pulmonary vascular remodeling, reduced plasma inflammatory markers, and changed key mitochondrial pathways in experimental PAH.
Keywords: pulmonary arterial hypertension; cardiovascular function; vascular remodeling; mitochondria; metabolism pulmonary arterial hypertension; cardiovascular function; vascular remodeling; mitochondria; metabolism

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MDPI and ACS Style

Onofre, M.E.d.S.F.; Santos, R.T.; Rocha, N.d.N.; Caldeira, D.d.A.F.; Silva, J.D.; Silva, C.M.d.; Melo, M.M.; Silva, M.M.A.d.; Pastor, C.R.S.; Batista, J.D.; et al. Mitochondrial Transplantation from Bone Marrow Mesenchymal Stromal Cells Combined with Sildenafil Attenuated Vascular Remodeling and Improved Right Ventricular Dysfunction in Experimental Pulmonary Arterial Hypertension. Int. J. Mol. Sci. 2026, 27, 1761. https://doi.org/10.3390/ijms27041761

AMA Style

Onofre MEdSF, Santos RT, Rocha NdN, Caldeira DdAF, Silva JD, Silva CMd, Melo MM, Silva MMAd, Pastor CRS, Batista JD, et al. Mitochondrial Transplantation from Bone Marrow Mesenchymal Stromal Cells Combined with Sildenafil Attenuated Vascular Remodeling and Improved Right Ventricular Dysfunction in Experimental Pulmonary Arterial Hypertension. International Journal of Molecular Sciences. 2026; 27(4):1761. https://doi.org/10.3390/ijms27041761

Chicago/Turabian Style

Onofre, Maria E. de S. F., Renata T. Santos, Nazareth de N. Rocha, Dayene de A. F. Caldeira, Johnatas D. Silva, Carla M. da Silva, Monique M. Melo, Mayck M. A. da Silva, Clara R. S. Pastor, Julia D. Batista, and et al. 2026. "Mitochondrial Transplantation from Bone Marrow Mesenchymal Stromal Cells Combined with Sildenafil Attenuated Vascular Remodeling and Improved Right Ventricular Dysfunction in Experimental Pulmonary Arterial Hypertension" International Journal of Molecular Sciences 27, no. 4: 1761. https://doi.org/10.3390/ijms27041761

APA Style

Onofre, M. E. d. S. F., Santos, R. T., Rocha, N. d. N., Caldeira, D. d. A. F., Silva, J. D., Silva, C. M. d., Melo, M. M., Silva, M. M. A. d., Pastor, C. R. S., Batista, J. D., Botelho, I. A., Veras, R. G., Serra, S. S. d. S., Zeidler, J. D., Rocco, P. R. M., Cruz, F. F., & Silva, P. L. (2026). Mitochondrial Transplantation from Bone Marrow Mesenchymal Stromal Cells Combined with Sildenafil Attenuated Vascular Remodeling and Improved Right Ventricular Dysfunction in Experimental Pulmonary Arterial Hypertension. International Journal of Molecular Sciences, 27(4), 1761. https://doi.org/10.3390/ijms27041761

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