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Article

Treatment with Sildenafil Promotes Angiogenesis and Modulates Immune Response in Ischemic Muscle Tissue

by
Amelie Kuhs
1,2,
Lisa Bobrowski
1,2,
Katharina Elbs
1,2,3,4,
Matthias Kübler
1,2,5,6,
Philipp Götz
1,2,7,
Christoph Arnholdt
1,2,8,
Manuel Lasch
1,2,9 and
Elisabeth Deindl
1,2,*
1
Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
2
Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
3
Department of Cardiovascular Diseases, TUM University Hospital German Heart Center, 80636 Munich, Germany
4
Center for Cardiovascular Research (DZHK), Munich Heart Alliance (MHA), Partner Site Munich, 81377 Munich, Germany
5
Deutsches Zentrum Immuntherapie (DZI) and Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
6
Department of Oral- and Cranio-Maxillofacial Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
7
Department of Otorhinolaryngology, Heidelberg University, 69120 Heidelberg, Germany
8
Department of Ophthalmology, Heidelberg University, 69120 Heidelberg, Germany
9
Department of Otorhinolaryngology, Head and Neck Surgery, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
*
Author to whom correspondence should be addressed.
Curr. Issues Mol. Biol. 2026, 48(3), 283; https://doi.org/10.3390/cimb48030283
Submission received: 9 February 2026 / Revised: 25 February 2026 / Accepted: 4 March 2026 / Published: 6 March 2026
(This article belongs to the Special Issue Molecular Mechanisms and Innovative Therapeutic Approaches in Inflammatory Diseases, Pioneering Precision Medicine Solutions, 2nd Edition)
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Abstract

Sildenafil, a selective phosphodiesterase-5 (PDE5) inhibitor, supports vascular remodeling, but its effects on angiogenesis and regeneration of ischemic muscle tissue are not fully understood. We investigated the function of sildenafil by employing a murine hindlimb model of ischemia, in which ischemia and angiogenesis is induced by femoral artery ligation (FAL) in the lower leg of mice. Then, 7 days after FAL or sham operation, gastrocnemius muscles of sildenafil-treated and control mice were isolated and processed for histological and immunofluorescence analyses. Sildenafil treatment led to reduced apoptotic areas within the ischemic tissue (ascertained via TUNEL assay) and increased angiogenesis, evidenced by a higher capillary-to-muscle fiber ratio and an augmented number of proliferating capillary cells (CD31+/CD45−/BrdU+), compared to controls. We observed a decrease in the total count of leukocytes (CD45+) in sildenafil-treated mice. Regarding macrophage infiltration, we found a reduced total number of macrophages (CD68+), along with a shift in macrophage polarization toward the pro-angiogenic and anti-inflammatory M2-like phenotype (CD68+/MRC1+). In summary, we show that sildenafil treatment contributes to angiogenesis and the regeneration of ischemic muscle tissue, most likely by attenuating inflammatory responses and influencing macrophage polarization in direction to regenerative M2-like polarized macrophages.
Keywords: sildenafil; PDE5 inhibitor; nitric oxide signaling; CGMP pathway; angiogenesis; ischemia; cardiovascular occlusive disease; endothelial cell proliferation; macrophage polarization; peripheral artery disease sildenafil; PDE5 inhibitor; nitric oxide signaling; CGMP pathway; angiogenesis; ischemia; cardiovascular occlusive disease; endothelial cell proliferation; macrophage polarization; peripheral artery disease

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MDPI and ACS Style

Kuhs, A.; Bobrowski, L.; Elbs, K.; Kübler, M.; Götz, P.; Arnholdt, C.; Lasch, M.; Deindl, E. Treatment with Sildenafil Promotes Angiogenesis and Modulates Immune Response in Ischemic Muscle Tissue. Curr. Issues Mol. Biol. 2026, 48, 283. https://doi.org/10.3390/cimb48030283

AMA Style

Kuhs A, Bobrowski L, Elbs K, Kübler M, Götz P, Arnholdt C, Lasch M, Deindl E. Treatment with Sildenafil Promotes Angiogenesis and Modulates Immune Response in Ischemic Muscle Tissue. Current Issues in Molecular Biology. 2026; 48(3):283. https://doi.org/10.3390/cimb48030283

Chicago/Turabian Style

Kuhs, Amelie, Lisa Bobrowski, Katharina Elbs, Matthias Kübler, Philipp Götz, Christoph Arnholdt, Manuel Lasch, and Elisabeth Deindl. 2026. "Treatment with Sildenafil Promotes Angiogenesis and Modulates Immune Response in Ischemic Muscle Tissue" Current Issues in Molecular Biology 48, no. 3: 283. https://doi.org/10.3390/cimb48030283

APA Style

Kuhs, A., Bobrowski, L., Elbs, K., Kübler, M., Götz, P., Arnholdt, C., Lasch, M., & Deindl, E. (2026). Treatment with Sildenafil Promotes Angiogenesis and Modulates Immune Response in Ischemic Muscle Tissue. Current Issues in Molecular Biology, 48(3), 283. https://doi.org/10.3390/cimb48030283

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