Vascular Pharmacology 140 (2021) 106873 Available online 13 May 2021 1537-1891/© 2021 Elsevier Inc. All rights reserved. Extracellular vesicles (EVs) in ischemic conditioning and angiogenesis: Focus on endothelial derived EVs Edoardo Alfì a , Cecilia Thairi a , Saveria Femmin` o b , Giuseppe Alloatti c , Francesco Moccia d , Maria F. Brizzi b , Pasquale Pagliaro a, * , Claudia Penna a a Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043 Orbassano, TO, Italy b Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy c Uni-Astiss, Polo Universitario Rita Levi Montalcini, 14100 Asti, Italy d Department of Biology and Biotechnology, University of Pavia, Laboratory of General Physiology, 27100 Pavia, Italy A R T I C L E INFO Keywords: Endothelial cells Cardioprotection Biomarkers Remote ischemic conditioning ABSTRACT During myocardial ischemia, timely reperfusion is critical to limit infarct area and the overall loss of cardiac contractile function. However, reperfusion further exacerbates the damage of the ischemic heart. This type of injury is known as ischemia-reperfusion injury (IRI). Ischemic conditioning is a procedure which consists of brief cycles of ischemia and reperfusion in order to protect the myocardium against IRI. Remote ischemic conditioning (RIC), namely transient brief episodes of ischemia at a remote site before a subsequent damaging ischemia/ reperfusion procedure of the target organ (e.g., the heart), protects against IRI. However, how the stimulus of RIC is transduced from the remote organ to the ischemic heart is still unknown. Recently, extracellular vesicles (EVs) have been proposed to have a role in the RIC procedure. The endothelium releases EVs and is also one of the tissues mostly exposed to EVs during their journey to the target organ. Moreover, EVs may have important roles in angiogenesis and, therefore, in the remodeling of post-ischemic organs. Here we analyze how EVs may contribute to the overall cardioprotective effect and the implication of the endothelium and its EVs in RIC mediated acute cardioprotection as well as in angiogenesis. 1. Introduction The paradigm of cardioprotection induced by ischemic pre- conditioning (IPC) was established by Murry and colleagues [1]. These authors demonstrated that brief cycles of 5 min coronary occlusion interspersed with 5 min of reperfusion immediately prior to 40 min of coronary occlusion were able to signifcantly reduce infarct size (IS). Subsequently remote ischemic conditioning (RIC) was described [2]. Unlike IPC, which protects only those districts directly subjected to initial ischemia by coronary occlusion, in RIC the ischemic insult is applied to distant areas within the heart or distant organs. Among distant organs limbs [3] are included. RIC gained popularity for this intriguing feature and it is believed a more applicable type of conditioning for cardioprotection in humans. RIC can be applied before ischemia, that is remote preconditioning (RIPC), during organ ischemia, namely remote per-conditioning (RIPerC) and/or after organ ischemia, that is remote post-conditioning (RIPostC). All these procedures, collectively known as RIC, showed similar cardioprotective effects [4]. Several evidence suggest that many organs can undergo RIC in order to protect the heart from ischemia/reperfusion (I/R) injury (IRI). Indeed, cardioprotection can be evoked by ischemic episodes in distant organs, such as liver [5], small intestine [6], and kidney [7]. Different interesting mechanisms have been proposed to explain the car- dioprotective effect of RIC [8] including: i) the RIC as a trigger of specifc mediators in the preconditioned remote organ/limb, ii) the transfer of such mediators from remote organ/limb to the heart, and fnally iii) the Abbreviations: AMI, Acute myocardial infarction; EC, Endothelial cells; ECFCs, Endothelial colony forming cells; EEs, Early endosomes; EPC, Endothelial pro- genitor cells; eNOS, Endothelial nitric oxide synthase; ESCRT, Endosomal sorting complex required for transport; EVs, Extracellular vesicles; HUVECs, Human umbilical vein endothelial cells; ILVs, Intraluminal vesicles; I/R, Ischemia reperfusion; IRI, Ischemia reperfusion injury; IPC, Ischemic preconditioning; LEs, Late endosomes; MMP, Matrix metalloprotease; MS, Metabolic syndrome; MSCs, Mesenchymal stem cells; MVBs, Multivesicular bodies; PI3K, Phosphoinositide-3-kinase; RIC, Remote ischemic conditioning; RIPC, Remote ischemic preconditioning; RIPerC, Remote ischemic perconditioning; RIPostC, Remote ischemic post conditioning. * Corresponding author. E-mail address: pasquale.pagliaro@unito.it (P. Pagliaro). Contents lists available at ScienceDirect Vascular Pharmacology journal homepage: www.elsevier.com/locate/vph https://doi.org/10.1016/j.vph.2021.106873 Received 10 April 2021; Received in revised form 7 May 2021; Accepted 11 May 2021