New Insights into the Reparative Angiogenesis after Myocardial Infarction

Abstract

Myocardial infarction (MI) causes massive loss of cardiac myocytes and injury to the coronary microcirculation, overwhelming the limited capacity of cardiac regeneration. Cardiac repair after MI is finely organized by complex series of procedures involving a robust angiogenic response that begins in the peri-infarcted border area of the infarcted heart, concluding with fibroblast proliferation and scar formation. Efficient neovascularization after MI limits hypertrophied myocytes and scar extent by the reduction in collagen deposition and sustains the improvement in cardiac function. Compelling evidence from animal models and classical in vitro angiogenic approaches demonstrate that a plethora of well-orchestrated signaling pathways involving Notch, Wnt, PI3K, and the modulation of intracellular Ca²⁺ concentration through ion channels, regulate angiogenesis from existing endothelial cells (ECs) and endothelial progenitor cells (EPCs) in the infarcted heart. Moreover, cardiac repair after MI involves cell-to-cell communication by paracrine/autocrine signals, mainly through the delivery of extracellular vesicles hosting pro-angiogenic proteins and non-coding RNAs, as microRNAs (miRNAs). This review highlights some general insights into signaling pathways activated under MI, focusing on the role of Ca²⁺ influx, Notch activated pathway, and miRNAs in EC activation and angiogenesis after MI.

Keywords: angiogenesis; cardiac repair; endothelial cell; heart infarction.

Figure 1

Signaling pathways activated in Endothelial Cells (ECs) after Myocardial Infarction (MI). During MI, ischemic cardiac tissue evokes the activation of HIF-1α, ROS, eNOS, Wnt, and JAK/STAT pathways in EC, which trigger the transcription of pro-angiogenic genes. Different heart cell populations (EC, EPC, cardiomyocytes, fibroblasts, macrophages) produce a high number of autocrine signals, including cytokines, growth factors such as VEGF, and non-coding RNAs, miRNAs, which regulate EC functions to rescue myocardium healing. VEGF induces the increase in intracellular Ca²⁺ concentration via store-operated Ca²⁺ entry (SOCE) through Orai and TRPC channels, which activates different transcription factors essential to ECs activity. VEGF increases DLL4 expression in EC, polarizing it to tip cell phenotype. In neighbor ECs, DLL4 activates Notch1 signaling, promoting the EC switch to stalk phenotype. Altogether, these events promote an increase in EC permeability, as well as in their proliferation, migration, and tube formation ability, hallmarks of angiogenesis. EPC: endothelial progenitor cells; ER: endoplasmic reticulum; DAG: directed acyclic graphs; DLL4: delta-like 4; eNOS: endothelial nitric oxide synthase; GF: growth factors; IP₃: 1,4,5-trisphosphate; IP₃R: IP₃ receptor; miRNAs: microRNAs; NICD: Notch intracellular domain; PLC: phospholipase C; ROS: reactive oxygen species; SERCA: sarcoendoplasmic reticulum (SR) calcium transport ATPase; VEGF: vascular endothelial growth factor; VEGFR1: VEGF receptor 1; VEGFR2: VEGF receptor 2.

Figure 2

Endothelial Progenitor Cells (EPCs) are essential in post-ischemic angiogenesis. Both types of EPCs, Myeloid angiogenic cells (MACs) and endothelial colony forming (ECFCs), are actively involved in reparative neovascularization after myocardial infarction (MI). MACs are key regulators for EPCs recruitment as they secrete a wide range of pro-angiogenic factors, as well as microRNAs (miRNAs), to stimulate cardiac endothelial cells (ECs). Circulating and resident ECFCs can differentiate into mature ECs and take part in new blood vessel formation.