Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction

Abstract

Background-The lymphatic system regulates interstitial tissue fluid balance, and lymphatic malfunction causes edema.The heart has an extensive lymphatic network displaying a dynamic range of lymph flow in physiology. Myocardial edema occurs in many cardiovascular diseases, eg, myocardial infarction (MI) and chronic heart failure, suggesting that cardiac lymphatic transport may be insufficient in pathology. Here, we investigate in rats the impact of MI and subsequent chronic heart failure on the cardiac lymphatic network. Further, we evaluate for the first time the functional effects of selective therapeutic stimulation of cardiac lymphangiogenesis post-MI. Methods and Results-We investigated cardiac lymphatic structure and function in rats with MI induced by either temporary occlusion (n=160) or permanent ligation (n=100) of the left coronary artery. Although MI induced robust, intramyocardial capillary lymphangiogenesis, adverse remodeling of epicardial precollector and collector lymphatics occurred, leading to reduced cardiac lymphatic transport capacity. Consequently, myocardial edema persisted for several months post-MI, extending from the infarct to noninfarcted myocardium. Intramyocardial-targeted delivery of the vascular endothelial growth factor receptor 3-selective designer protein VEGF-C C152S , using albumin-alginate microparticles, accelerated cardiac lymphangiogenesis in a dose-dependent manner and limited precollector remodeling post-MI. As a result, myocardial fluid balance was improved, and cardiac inflammation, fibrosis, and dysfunction were attenuated. Conclusions-We show that, despite the endogenous cardiac lymphangiogenic response post-MI, the remodeling and dysfunction of collecting ducts contribute to the development of chronic myocardial edema and inflammationaggravating cardiac fibrosis and dysfunction. Moreover, our data reveal that therapeutic lymphangiogenesis may be a promising new approach for the treatment of cardiovascular diseases. deleterious effects, including induction of blood vascular rarefaction and dysfunction and stimulation of cardiac fibrosis, contributing to the development of chronic heart failure . 14 Furthermore, many inflammatory mediators, and oxygen radicals generated during inflammation, as well, negatively affect lymphatic function, causing impairment of lymph flow and initiation of lymph edema and chronic inflammation. 15,16 It is noteworthy that clinically detectable myocardial edema, extending beyond the infarct zone, may persist for up to 6 to 12 months post-myocardial infarction (MI) in humans, which is suggestive of lymphatic insufficiency. 17,18Whether cardiac lymphatic dysfunction occurs after myocardial injury, and the impact this may have on myocardial fluid balance and cardiac inflammation, remains to be investigated. Moreover, although the advent of molecular lymphatic markers has fueled investigations into lymphatic anatomy, function, and growth in many organs, 19-21 only a handful of articles have assessed lymphangiogenesis in the heart. It was rec...

Mesenchymal stem cell‐loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium

“…Lymphangiogenesis occurs after MI 35. Enhancement of lymphangiogenesis may reduce myocardial oedema and cardiac fibrosis, promoting improvement in cardiac function 36, 37. Our data show that lymphatic capillaries in the infarcted heart increased in cell patch group than that in patch‐ or MSC‐only groups.…”

Therapeutic lymphangiogenesis after myocardial infarction: vascular endothelial growth factor-C paves the way

“…In this regard, several groups independently observed a substantial increase in the numbers of intra-myocardial lymphatic capillaries and pre-collecting subepicardial lymphatics in human (11,13,14), mouse (15,16) and rat (1,17,18) cardiac tissues, predominantly in the periinfarcted area. The time-course of the lymphatic vessel appearance conspicuously coincides with the commencement of the reparatory stages of wound healing in the infarcted heart, while post-MI lymphangiogenesis is peaking during the development of the fibrotic scar replacing the lost myocardium; and, intriguingly, the CLVs, once formed, seem to persist in the scarred tissue (14,15,18).…”

“…The new excellent study by Henri and colleagues published in the April 12 issue of the Circulation journal addresses an important issue of the involvement of lymphatic vasculature in the restoration of cardiac function after infarction (1).…”

“…On the other hand, as discussed below, there are appealing evidences that by reducing inflammation via post-MI lymphangiogenesis one can avert fibrosis, improve myocardial integrity and achieve a better restoration of cardiac function (1,15,19).…”

“…In their present study, Henri et al carried out an exhaustive analysis of the impact of therapeutic lymphangiogenesis that is stimulation of lymphatic vessel growth in the infarcted heart, on the development of myocardial edema and efficacy of cardiac contractility after MI (1). To this end, the authors used rat models of temporary and permanent occlusions of the left coronary artery anterior descending branch, which recapitulate some aspects of human cardiovascular diseases and chronic heart failure.…”