Lymphatic and Immune Cell Cross-Talk Regulates Cardiac Recovery After Experimental Myocardial Infarction

Abstract

<jats:sec> <jats:title>Objective:</jats:title> <jats:p>Lymphatics play an essential pathophysiological role in promoting fluid and immune cell tissue clearance. Conversely, immune cells may influence lymphatic function and remodeling. Recently, cardiac lymphangiogenesis has been proposed as a therapeutic target to prevent heart failure after myocardial infarction (MI). We investigated the effects of gene therapy to modulate cardiac lymphangiogenesis post-MI in rodents. Second, we determined the impact of cardiac-infiltrating T cells on lymphatic remodeling in the heart.</jats:p> </jats:sec> <jats:sec> <jats:title>Approach and Results:</jats:title> <jats:p> Comparing adenoviral versus adeno-associated viral gene delivery in mice, we found that only sustained VEGF (vascular endothelial growth factor)-C <jats:sub>C156S</jats:sub> therapy, achieved by adeno-associated viral vectors, increased cardiac lymphangiogenesis, and led to reduced cardiac inflammation and dysfunction by 3 weeks post-MI. Conversely, inhibition of VEGF-C/-D signaling, through adeno-associated viral delivery of soluble VEGFR3 (vascular endothelial growth factor receptor 3), limited infarct lymphangiogenesis. Unexpectedly, this treatment improved cardiac function post-MI in both mice and rats, linked to reduced infarct thinning due to acute suppression of T-cell infiltration. Finally, using pharmacological, genetic, and antibody-mediated prevention of cardiac T-cell recruitment in mice, we discovered that both CD4 <jats:sup>+</jats:sup> and CD8 <jats:sup>+</jats:sup> T cells potently suppress, in part through interferon-γ, cardiac lymphangiogenesis post-MI. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p> We show that resolution of cardiac inflammation after MI may be accelerated by therapeutic lymphangiogenesis based on adeno-associated viral gene delivery of VEGF-C <jats:sub>C156S</jats:sub> . Conversely, our work uncovers a major negative role of cardiac-recruited T cells on lymphatic remodeling. Our results give new insight into the interconnection between immune cells and lymphatics in orchestration of cardiac repair after injury. </jats:p> </jats:sec>

VEGF‐C/VEGFR‐3 axis protects against pressure‐overload induced cardiac dysfunction through regulation of lymphangiogenesis

“…33 Conversely, inhibition of VEGF-C/D signaling reduces infarct lymphangiogenesis and T-cell infiltration but improves cardiac function post-MI in animals. 34 Furthermore, systemic blockade of VEGF-C/D or VEGFR-3 in db/db mice significantly attenuates obesity-induced insulin resistance, adipose tissue M1 macrophage infiltration, and hepatic lipid accumulation. 35 LYVE-1 is highly expressed in lymphatic capillaries and is required for leukocyte clearance under inflammatory conditions.…”

“…VEGF‐C and VEGF‐D are as potent stimulators of lymphangiogenesis that participate in cardiac tissue generation and tissue repair, and VEGF‐D can compensate for loss of VEGF‐C in some contexts 33 . Conversely, inhibition of VEGF‐C/D signaling reduces infarct lymphangiogenesis and T‐cell infiltration but improves cardiac function post‐MI in animals 34 . Furthermore, systemic blockade of VEGF‐C/D or VEGFR‐3 in db/db mice significantly attenuates obesity‐induced insulin resistance, adipose tissue M1 macrophage infiltration, and hepatic lipid accumulation 35 .…”

Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension

“…Recent studies indicated that the lymphatic vasculature, a traditionally-neglected target for therapeutic interventions, plays an important role in the pathogenesis of cardiovascular diseases, and enhancing lymphangiogenesis could be beneficial for acute cardiac injuries ( Henri et al, 2016 ; Houssari et al, 2020 ; Huang et al, 2017 ; Klotz et al, 2015 ; Liu and Oliver, 2019 ; Shimizu et al, 2018 ; Tatin et al, 2017 ; Trincot et al, 2019 ; Vieira et al, 2018 ; Vivien et al, 2019 ). However, the role of the lymphatic vasculature in chronic cardiac dysfunction remains to be elucidated.…”

“…Recently, cardiac lymphatics have emerged as a new therapeutic target for acute cardiac injuries. Several studies have demonstrated using rodent models that therapeutic lymphangiogenesis reduced myocardial edema and fibrosis, resolved inflammation, and improved cardiac function after myocardial infarction ( Henri et al, 2016 ; Houssari et al, 2020 ; Klotz et al, 2015 ; Tatin et al, 2017 ; Trincot et al, 2019 ; Vieira et al, 2018 ) or ischemia and reperfusion injury ( Shimizu et al, 2018 ). These studies in aggregate concluded that the improvement in cardiac function was due to local proliferation of lymphatic vessels at the site of injury in response to lymphangiogenic therapies.…”

Regulation and impact of cardiac lymphangiogenesis in pressure-overload-induced heart failure

“…It should be noted that following MI there is significant destruction, rarefaction, and dysfunction of cardiac lymphatics, whereas after pressure-overload cardiac lymphatics were comparably less altered. In particular, we recently demonstrated that poor cardiac lymphangiogenesis post-MI was linked to elevated interferon (IFN)-γ, in part produced by cardiac-infiltrating T cells 8 . In contrast, previous studies have indicated a predominant Th2-type immune response in Balb/c mice, with low cardiac expression of IFN-γ and elevated IL-4, leading to dilated cardiomyopathy in response to chronic arterial hypertension 37 .…”