Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction
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, e.g. myocardial infarction (MI) and chronic heart failure (CHF), suggesting that cardiac lymphatic transport may be insufficient in pathology. Here, we investigate in rats the impact of MI and subsequent CHF 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. While MI induced robust, intramyocardial capillary lymphangiogenesis, adverse remodeling of epicardial pre-collector 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 non-infarcted myocardium. Intramyocardial targeted delivery of the VEGFR3-selective designer protein VEGF-CC152S, using albumin-alginate microparticles, accelerated cardiac lymphangiogenesis in a dose-dependent manner and limited pre-collector remodeling post-MI. As a result, myocardial fluid balance was improved and cardiac inflammation, fibrosis and dysfunction attenuated.
Conclusions—We show that despite the endogenous cardiac lymphangiogenic response post-MI, the remodeling and dysfunction of collecting ducts contribute to installment of chronic myocardial edema and inflammation aggravating cardiac fibrosis and dysfunction. Moreover, our data reveal that therapeutic lymphangiogenesis may be a promising new approach for the treatment of cardiovascular diseases.
- cardiac lymphatics
- cardiac remodeling
- myocardial edema
- lymphatic capillary
- ischemic heart failure
- Received October 27, 2015.
- Revision received February 5, 2016.
- Accepted February 19, 2016.