{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T23:41:04Z","timestamp":1772840464821,"version":"3.50.1"},"reference-count":77,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"F\u00f6rderprogramm f\u00fcr Forschung und Lehre","award":["12\/2021"],"award-info":[{"award-number":["12\/2021"]}]},{"name":"F\u00f6rderprogramm f\u00fcr Forschung und Lehre","award":["12\/2019"],"award-info":[{"award-number":["12\/2019"]}]},{"name":"LMUexcellent Knowledge Transfer Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Arteriogenesis, the growth of pre-existing arterioles into functional collateral arteries, represents a key adaptive response to severe arterial stenosis. This process is driven by hemodynamic forces and a tightly coordinated inflammatory cascade. Here, we investigated the effects of pharmacological stimulation of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling pathway using the phosphodiesterase-5 (PDE5) inhibitor Sildenafil on collateral vessel growth in a murine model of femoral artery ligation (FAL). Flow cytometric analyses revealed that Sildenafil treatment significantly enhanced platelet\u2013leukocyte aggregate formation, a prerequisite for the subsequent initiation of a localized perivascular inflammation. Histological and immunofluorescence analyses further demonstrated a marked increase in mast cell recruitment and degranulation at early time points (days 1 and 3 post-FAL). In addition, Sildenafil promoted perivascular macrophage accumulation on days 3 and 7, with a pronounced shift toward an M2-like pro-regenerative polarization state, ultimately resulting in the enhanced proliferation of vascular cells and the enlargement of collateral diameters. Together, these findings identify Sildenafil as a potent enhancer of arteriogenesis through coordinated immune cell activation, stimulating vascular cell proliferation along with positive collateral outward remodeling. Thus, Sildenafil emerges as a promising therapeutic candidate to promote collateral artery growth in cardiovascular occlusive diseases.<\/jats:p>","DOI":"10.3390\/ijms27020985","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T13:02:07Z","timestamp":1768914127000},"page":"985","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Repurposing PDE5-Inhibitors: Sildenafil Drives Arteriogenesis via Localized Regenerative Inflammation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3734-3666","authenticated-orcid":false,"given":"Katharina","family":"Elbs","sequence":"first","affiliation":[{"name":"Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"},{"name":"Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 82152 Planegg, Germany"},{"name":"Department of Cardiovascular Diseases, TUM University Hospital German Heart Center, 80636 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Bobrowski","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"},{"name":"Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 82152 Planegg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Arnholdt","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"},{"name":"Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 82152 Planegg, Germany"},{"name":"Department of Ophthalmology, University of Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"K\u00fcbler","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"},{"name":"Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 82152 Planegg, Germany"},{"name":"Deutsches Zentrum Immuntherapie (DZI), Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"},{"name":"Department of Oral- and Cranio-Maxillofacial Surgery, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philipp","family":"G\u00f6tz","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"},{"name":"Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 82152 Planegg, Germany"},{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4974-9783","authenticated-orcid":false,"given":"Michael R.","family":"Rohrmoser","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"},{"name":"Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 82152 Planegg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4852-831X","authenticated-orcid":false,"given":"Daphne","family":"Merkus","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"},{"name":"Department of Experimental Cardiology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"},{"name":"Center for Cardiovascular Research (DZHK), Munich Heart Alliance (MHA), Partner Site Munich, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Lasch","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"},{"name":"Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 82152 Planegg, Germany"},{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Munich, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2134-0966","authenticated-orcid":false,"given":"Elisabeth","family":"Deindl","sequence":"additional","affiliation":[{"name":"Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"},{"name":"Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 82152 Planegg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e058418","DOI":"10.1136\/bmjopen-2021-058418","article-title":"Safety and feasibility study of non-invasive robot-assisted high-intensity focused ultrasound therapy for the treatment of atherosclerotic plaques in the femoral artery: Protocol for a pilot study","volume":"12","author":"Simons","year":"2022","journal-title":"BMJ Open"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hummitzsch, L., Voelckers, L., Rusch, M., Cremer, J., Albrecht, M., 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