In aging mice, cardiac lymphatic vessels thin out before the heart scars and thickens, and the cause traces to a nuclear form of IL-33 switched on by T-cell signaling
In aging mice, cardiac lymphatic vessels thin out before the heart scars and thickens, and the cause traces to a nuclear form of IL-33 switched on by T-cell signaling
On September 15, Stefanie Dimmeler's laboratory at Goethe University Frankfurt published a study in Nature Cardiovascular Research describing a vicious cycle: aging immune cells in the heart destroy its drainage network, and without drainage the same cells become trapped in the tissue. VEGF-C partially restores lymphatic vessels and reduces inflammation in aged mice but does not recover the heart's ability to relax between beats.
Cardiac lymphatic vessels drain excess fluid and spent proteins and carry immune cells to lymph nodes. In mice aged 18 to 22 months the heart contains markedly fewer lymphatic vessels than at three months; a parallel decline was found in humans through cardiac gene-expression data. Drainage fails first: by 16 months, fibrinogen, a blood protein normally cleared by these vessels, accumulates in the tissue. Edema appears from 18 months onward, and wall thickening and scarring only at 18 to 20 months.
To test causality, the authors depleted the lymphatic network in young healthy mice by deleting the growth-receptor gene VEGFR3 or by injecting a virus that intercepts its signal. Hearts of young mice acquired features of aged ones: macrophages and fibrinogen accumulated, and severe depletion impaired cardiac relaxation. The authors attribute this to fluid: without drainage it presses on the interstitial space and prevents the muscle from relaxing even in the absence of overt fibrosis.
Single-cell RNA sequencing of endothelial cells showed that IL-33 gene activity rises most sharply with age in lymphatic cells, specifically its nuclear form, which inhibits cell division and triggers cell death. This resolves a long-standing debate about the role of IL-33: in earlier studies its secreted form stimulated vessel growth.
The nuclear form of IL-33 is activated by interferon-gamma signaling. Aging T-cells and NK cells (natural killer cells) secrete more of this cytokine, and T-cells in particular move into closer physical proximity with cardiac lymphatic vessels as the animal ages. The cycle closes: immune cell aging activates a protein that destroys the drainage network, and the weakened network in turn prevents those same cells from leaving the tissue.
Of the growth factors tested, VEGF-C and reelin both promoted vessel proliferation, but only VEGF-C suppressed the interferon-driven rise in IL-33. VEGF-C is the lymphatic growth factor first identified by Kari Alitalo, the Finnish scientist who is a co-author on this paper.
Delivery of the VEGF-C gene to aged mice increased vessel density and reduced macrophage accumulation, but over eight weeks it did not correct the impaired cardiac relaxation. The lymphatic component proved to be only one part of the broader aging process.
Three years earlier the same laboratory showed in Science another route of degradation in the aging heart: loss of ventricular nerve fibers caused by suppression of miR-145 and increased semaphorin-3A, a process reversible by clearing senescent cells. Together the two studies outline a shared picture. The aging heart progressively loses its supporting networks, first the neural one and now the lymphatic one, and this loss appears to be what sets off the familiar hallmarks of cardiac aging.
The authors frame their conclusion cautiously:
Our data show that cardiac lymphatic vessels are an early contributor to inflammation and possibly to functional decline in the aging heart
Impaired cardiac relaxation, the hallmark of heart failure with preserved ejection fraction (a condition common in the elderly), still lacks a treatment proven to reduce mortality. This study identifies two targets for the condition, the VEGFR3 pathway and nuclear IL-33, and shows that modulating them in mice already partially alters the course of cardiac aging.