Cysteine-rich with EGF-like domains 2 – Exodosis and angiogenesis after myocardial infarction

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Acute myocardial infarction inflicts massive injury to the coronary microcirculation leading to vascular disintegration and capillary rarefication. Within days, a new vascular system develops in the infarct area and helps limiting the extent of scar formation and left ventricular remodelling. The endoplasmic reticulum (ER) plays a pivotal role in the folding, posttranslational modification, and secretion of many autocrine- and paracrine-acting angiogenic growth factors. However, ischemia-reperfusion injury and the increased secretory activity after myocardial infarction may overwhelm ER homeostasis (ER stress). Binding to KDEL receptors determines whether proteins are retained in the ER/Golgi system or are secreted. Accordingly, many ER-resident chaperones possess a classical, C-terminal Lys-Asp-Glu-Leu (KDEL) ER retention signal. Growth factors lacking this motif are secreted. Conversely, proteins with a weak ER retention signal are retained in the ER under basal conditions and are preferentially secreted under ER stress (exodosis). We propose that exodosis provides a mechanism to stimulate angiogenesis specifically in the infarct area. We have performed a single endothelial cell RNA-sequencing-based bioinformatic secretome analysis in the infarct area of mice to identify previously uncharacterised growth factors produced by ER-stressed endothelial cells. We thus identified cysteine-rich with EGF-like domains 2. CRELD2 has a weak ER retention signal (REDL) and is strongly induced during ER stress. Based on our preliminary data, we postulate that endothelial cells release CRELD2 in the infarct area via exodosis to stimulate angiogenesis and wound healing in an autocrine manner. Both hypotheses will be investigated in our project. We intend to measure the expression and secretion of CRELD2 in mice and humans with acute myocardial infarction. We want to study angiogenesis and wound healing after myocardial infarction in globally or conditionally Creld2-deficient mice. We aim to define if CRELD2 acts as an ER resident and/or secreted protein in the infarct area and to explore the therapeutic potential of recombinant CRELD2 after myocardial infarction. Finally, we plan to identify the putative CRELD2 cell surface receptor in endothelial cells and to characterise downstream alterations in the phosphoproteome. Using CRELD2 as an example, our project shall establish exodosis as an important stimulus of angiogenesis and wound healing after myocardial infarction.