Vegfc/d-dependent regulation of the lymphatic vasculature during cardiac regeneration is influenced by injury context

Abstract

The lymphatic vasculature mediates essential physiological functions including fluid homeostasis, lipid and hormone transport, and immune cell trafficking. Recent studies have suggested that promoting lymphangiogenesis enhances cardiac repair following injury, but it is unknown whether lymphangiogenesis is required for cardiac regeneration. Here, we describe the anatomical distribution, regulation, and function of the cardiac lymphatic network in a highly regenerative zebrafish model system using transgenic reporter lines and loss-of-function approaches. We show that zebrafish lacking functional vegfc and vegfd signaling are devoid of a cardiac lymphatic network and display cardiac hypertrophy in the absence of injury, suggesting a role for these vessels in cardiac tissue homeostasis. Using two different cardiac injury models, we report a robust lymphangiogenic response following cryoinjury, but not following apical resection injury. Although the majority of mutants lacking functional vegfc and vegfd signaling were able to mount a full regenerative response even in the complete absence of a cardiac lymphatic vasculature, cardiac regeneration was severely impaired in a subset of mutants, which was associated with heightened pro-inflammatory cytokine signaling. These findings reveal a context-dependent requirement for the lymphatic vasculature during cardiac growth and regeneration.

Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration

“…We cannot rule out a direct effect on elevating the immune response with blockade of Vegfc-signal, but the resulting shift has a potent negative effect on the continuing regenerative environment of the tissue, while not directly effecting cardiomyocyte proliferation, epicardial activation, coronary vessel revascularization or heart structure and morphology (Figure 6). Consistent with our studies using sFlt4, recently it has been reported that a vegfd -mutation in a vegfc -hypermorphic background can also limit the extension of the cardiac lymphatic vessels down the ventricle while not affecting coronary vessels (Vivien et al, 2019). Further, almost half of the vegfc/d mutant zebrafish surviving to adulthood fail to complete regeneration by 180dpc (Vivien et al, 2019).…”

Lymphatic vessels help mend broken hearts

“…The formation of the new lymphatic vessels and structures seems to follow the demand for fluid drainage from the ventricular tissue, which increases following myocardial damage. Thus, lymphatic vessels in the heart create an environment favorable to scar resolution and regeneration (which is consistent with a recent study by Vivien et al, 2019).…”

Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis

“…In mouse embryos, venous derived lymphatics were shown to give rise to the vessels paralleling the coronaries, while non-venous, Tie2-negative yolk sac derived progenitors (Klotz et al, 2015) contribute to the formation of PROX1+ LECs in the developing heart. Recently, three independent studies (Gancz et al, 2019b;Harrison et al, 2019;Vivien et al, 2019) described the development of cardiac lymphatics in zebrafish as well as their role during cardiac regeneration. Interestingly, in addition to conventional lymphatic vessels spanning the cardiac ventricle, Gancz et al (2019b) reported the presence of isolated prox1+, lyve1b+, mrc1+ and flt4+ LEC clusters in the zebrafish heart that developed initially into single capillaries, and later on connected to the existing lymphatic plexus.…”