Shashank Bhagavatula

Background: Cardiovascular diseases cause approximately 17.9 million deaths annually, projected to exceed 23.6 million by 2030.⁶ Myocardial infarction (MI) triggers irreversible cardiomyocyte loss followed by persistent inflammation and fibrosis that can progress to heart failure; while current treatments, including percutaneous coronary intervention, ACE inhibitors, and beta-blockers, address acute ischemia, they inadequately target the maladaptive remodeling that follows.¹ Cardiac lymphatic vessels play a critical and underappreciated role in post-MI repair by draining excess fluid, clearing immune cells, and secreting paracrine signaling molecules called lymphangiocrines such as CXCL12, Reelin (RELN), adrenomedullin (AM), and CCL2 that coordinate immune recruitment, inflammation resolution, and spatial tissue remodeling.^2-4,8 Despite growing recognition of this biology, no defined mechanistic understanding of how the CXCL12-CXCR4 axis specifically regulates spatial post-MI remodeling exists, and no targeted therapeutic strategy has yet emerged.⁹

Objective: This narrative review examines key lymphangiocrine mechanisms in post-MI cardiac repair and evaluates the CXCL12-CXCR4 axis as a candidate spatially targeted therapeutic strategy.

Search Methods: PubMed and Google Scholar were searched from 2017 to 2026 using MeSH terms and keywords including “lymphangiocrine,” “cardiac lymphatics,” “myocardial infarction remodeling,” “CXCL12-CXCR4,” “lymphangiogenesis,” “Reelin,” “adrenomedullin,” and “CCL2.”

Results: Liu et al. used mass spectrometry proteomics to identify RELN as a key LEC-secreted lymphangiocrine; AAV-mediated RELN delivery in adult post-MI mice reduced cardiomyocyte apoptosis and infarct fibrosis, improving cardiac function without restoring proliferation.¹ Trincot et al. demonstrated that adrenomedullin, an epicardial-derived lymphangiocrine, promotes post-MI cardiac lymphangiogenesis via connexin 43 (Cx43)-mediated LEC gap junction coupling; verapamil, an FDA-approved drug, improved LEC coupling in vitro, and sex-specific differences in baseline cardiac lymphatics were observed.² Houssari et al. showed that only sustained AAV-VEGF-C delivery achieved lasting lymphangiogenesis, reduced pro-inflammatory macrophages, and improved cardiac function; paradoxically, blocking lymphatic growth suppressed T-cell infiltration, revealing that CD4⁺ and CD8⁺ T cells inhibit lymphatic repair via IFN-γ in a negative feedback loop.³ Li et al. demonstrated that LEC-expressed S1PR1 activates ERK signaling to upregulate CCL2, enabling macrophage chemotaxis into lymphatic vessels for clearance during the post-MI reparative phase.⁴ Deng et al. established that LEC-CCL2 serves a dual role: recruiting macrophages for lymphatic clearance and activating an AKT/ETS1 signaling cascade to upregulate VEGF-C, driving lymphangiogenesis via positive autocrine feedback.⁵

Conclusion: Cardiac LECs are active orchestrators of post-MI repair through a diverse lymphangiocrine secretome encompassing RELN, AM, S1P-driven CCL2, and the CXCL12-CXCR4 axis, collectively regulating cardiomyocyte survival, macrophage trafficking, and the balance between regeneration and fibrosis. Key translational barriers include the T-cell/IFN-γ negative feedback loop and sex-specific lymphatic differences requiring sex-stratified therapeutic design. Future directions include testing verapamil clinically, combining AAV-VEGF-C therapy with immunomodulation, pharmacological targeting of the AKT/ETS1/VEGF-C cascade, and CXCL12-CXCR4 antagonism for spatial remodeling control, collectively supporting a paradigm shift toward LEC-targeted therapy to improve outcomes after myocardial infarction.

Works Cited

1. Liu X, De la Cruz E, Gu X, et al. Lymphoangiocrine signals promote cardiac growth and repair. Nature. 2020;588(7839):705-711. doi:10.1038/s41586-020-2998-x
2. Trincot CE, Xu W, Zhang H, et al. Adrenomedullin induces cardiac lymphangiogenesis after myocardial infarction and regulates cardiac edema via connexin 43. Circ Res. 2019;124(1):101-113. doi:10.1161/CIRCRESAHA.118.313835
3. Houssari M, Dumesnil A, Tardif V, et al. Lymphatic and immune cell cross-talk regulates cardiac recovery after experimental myocardial infarction. Arterioscler Thromb Vasc Biol. 2020;40(7):1722-1737. doi:10.1161/ATVBAHA.120.314370
4. Li Q, Zhou C, Zhao K, et al. Lymphatic endothelial sphingosine 1-phosphate receptor 1 enhances macrophage clearance via lymphatic system following myocardial infarction. Front Cardiovasc Med. 2022;9:872102. doi:10.3389/fcvm.2022.872102
5. Deng S, Zhao K, Cai Z, et al. Lymphatic endothelial C-C motif chemokine ligand 2 enhances lymphangiogenesis and lymphatic clearance of macrophages following myocardial infarction. J Am Heart Assoc. 2026;15(1):e039153. doi:10.1161/JAHA.124.039153
6. Klaourakis K, Vieira JM, Riley PR. The evolving cardiac lymphatic vasculature in development, repair and regeneration. Nat Rev Cardiol. 2021;18(5):368-379. doi:10.1038/s41569-020-00489-x
7. Ji RC. The role of lymphangiogenesis in cardiovascular diseases and heart transplantation. Heart Fail Rev. 2022;27(5):1837-1856. doi:10.1007/s10741-021-10188-5
8. Kurup S, Tan C, Kume T. Cardiac and intestinal tissue conduct developmental and reparative processes in response to lymphangiocrine signaling. Front Cell Dev Biol. 2023;11:1329770. doi:10.3389/fcell.2023.1329770
9. Murad HAS, Rafeeq MM, Alqurashi TMA. Role and implications of the CXCL12/CXCR4/CXCR7 axis in atherosclerosis: still a debate. Ann Med. 2021;53(1):1598-1612. doi:10.1080/07853890.2021.1974084