Lymphangiogenesis contributes to exercise-induced physiological cardiac growth.
Level 5 - mechanism / opinion, no new human data
Animal and in vitro mechanistic study without human clinical data
PubMed 35218948 · doi:10.1016/j.jshs.2022.02.005
What was done
Adult C57BL6/J mice underwent a 3-week swimming exercise protocol to induce physiological cardiac growth, with or without oral administration of the vascular endothelial growth factor receptor 3 (VEGFR3) inhibitor SAR131675. In vitro, isolated neonatal rat cardiomyocytes were treated with conditioned medium from human dermal lymphatic endothelial cells (LECs) with or without SAR131675 to assess cardiomyocyte proliferation (Ki67 expression), hypertrophy, and downstream signaling pathways including IGF-1, Reelin, AKT, C/EBPβ, and CITED4.
What was found
Swimming exercise induced physiological cardiac growth accompanied by increased cardiac lymphatic vessel density and upregulated LYVE-1, Podoplanin, and VEGFR3 expression. Pharmacological inhibition of VEGFR3 via SAR131675 attenuated exercise-induced cardiac growth, blunting hypertrophy and reducing cardiomyocyte Ki67 proliferation markers alongside decreased LYVE-1 and Podoplanin levels (no numerical values or effect sizes were reported in the abstract). In vitro, LEC-conditioned medium contained elevated IGF-1 and Reelin, promoting cardiomyocyte hypertrophy and proliferation through AKT activation, C/EBPβ reduction, and CITED4 upregulation; SAR131675 treatment blocked these effects.
Why it matters
The study establishes that cardiac lymphangiogenesis and lymphatic endothelial paracrine signaling are mechanistically required for physiological exercise-induced cardiac remodeling. This identifies specific molecular pathways (VEGFR3, IGF-1, Reelin, and C/EBPβ-CITED4) that regulate non-pathological cardiac growth.
Limits
The study is entirely preclinical, relying on a rodent swimming model and in vitro cell culture, meaning findings cannot be directly generalized to humans. The abstract omits sample sizes (n), exact quantitative measurements, and variance or confidence intervals. The durability of these changes after exercise cessation and functional in vivo hemodynamic consequences were not detailed.
Cited by
- partial Much of the cardiovascular benefit of aerobic exercise for the heart is mediated by stimulating the growth and health of lymphatic vessels rather than acting directly on heart cells.
- supports Cardiovascular exercise promotes lymphangiogenesis, the growth of new lymphatic vessels innervating the heart.
- supports Lymphangiogenesis contributes to exercise-induced physiological cardiac growth.