PhD Scientific Days 2025

Theoretical and Translational Medicine II.

Bidirectional Vasoactive Effects of the C3a Anaphylatoxin in Health and Vascular Disease

Name of the presenter

Babay Imre

Institute/workplace of the presenter

Institute of Translational Medicine

Authors

Imre Babay¹, Nóra Melinda Kerkovits¹, Mónika Kosztelnik^1,5, Csillag Virág Tóth¹, Balázs Besztercei¹, Anna Janovicz^1,5, Aliz Majer¹, Krisztina Vén¹, Éva Ruisanchez^1,5, Gábor Szénási¹, Tamás Radovits², Ágnes Szappanos^2,6, József Balla³, Gábor Csányi⁴, Béla Merkely², Péter Sótonyi², Zoltán Benyó^1,5

1: Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
2: Heart and Vascular Center, Semmelweis University, Budapest, Hungary
3: Institute of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
4: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
5: HUN-REN-SU Cerebrovascular and Neurocognitive Disease Research Group, Budapest, Hungary
6: Department of Rheumatology and Clinical Immunology, Semmelweis University, Budapest, Hungary

Text of the abstract

Introduction:
The complement system has been increasingly recognized as a key factor in the development of cardiovascular diseases (CVD), although its exact molecular mechanisms and signaling pathways remain unclear.

Aims:
This study examines the vasoactive effects of the C3a anaphylatoxin in murine thoracic aorta and human coronary arteries, with a focus on its modulation during angiotensin II (Ang II)-induced vascular dysfunction and ischemic heart disease (IHD).

Methods:
C3a-induced vascular responses were studied in isolated murine and human vessels using myography. The roles of the endothelium and adventitia in mediating the effects of C3a were assessed, along with the involvement of cyclooxygenase-1 (COX1) and thromboxane prostanoid (TP) receptors. C3a receptor (C3aR) expression was evaluated after Ang II treatment in mice and in coronary arteries from IHD patients. All procedures involving animals and human tissues were conducted with appropriate ethical approval.

Results:
C3a induced both endothelium-dependent vasodilation and a marked vasoconstrictive response in murine vessels, the latter of which was abolished by removal of the adventitia. This vasoconstriction was associated with thromboxane A2 (TXA2) production and was absent in COX1- or TP-deficient mice. Ang II treatment for two weeks significantly upregulated C3aR expression and enhanced C3a-induced vasoconstriction, which remained COX1- and TP-dependent. Human coronary arteries also showed COX1- and TP-mediated vasoconstriction in response to C3a, with increased C3aR expression and reactivity observed in IHD patients.

Conclusion:
This study is the first to demonstrate TXA2-mediated C3aR signaling in both murine and human vasculature, showing its upregulation under pathological conditions. This pathway may serve as a potential target for therapeutic strategies in CVD.

Funding:
This study was supported by NKFIH K-135683, K-139230, K-149634, K-149734, and K-151053, as well as by 2020-1.1.6-JÖVŐ-2021-00010, TKP2021-EGA-25, and EFOP-3.6.3-VEKOP-16-2017-00009 grants, and by the 2024-2.1.1-EKÖP-2024-00004 University Research Scholarship Program of the Ministry for Culture and Innovation of Hungary, as well as the 2024-1.2.3-HU-RIZONT-2024-00059 program financed by the NRDI Fund of Hungary.