VEGF‐A promotes angiogenesis after acute myocardial infarction through increasing ROS production and enhancing ER stress‐mediated autophagy

Abstract

Proangiogenesis is generally regarded as an effective approach for treating ischemic heart disease. Vascular endothelial growth factor (VEGF)‐A is a strong and essential proangiogenic factor. Reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy are implicated in the process of angiogenesis. This study is designed to clarify the regulatory mechanisms underlying VEGF‐A, ROS, ER stress, autophagy, and angiogenesis in acute myocardial infarction (AMI). A mouse model of AMI was successfully established by occluding the left anterior descending coronary artery. Compared with the sham‐operated mice, the microvessel density, VEGF‐A content, ROS production, expression of vascular endothelial cadherin, positive expression of 78 kDa glucose‐regulated protein/binding immunoglobulin protein (GRP78/Bip), and LC3 puncta in CD31‐positive endothelial cells of the ischemic myocardium were overtly elevated. Moreover, VEGF‐A exposure predominantly increased the expression of beclin‐1, autophagy‐related gene (ATG) 4, ATG5, inositol‐requiring enzyme‐1 (IRE‐1), GRP78/Bip, and LC3‐II/LC3‐I as well as ROS production in the human umbilical vein endothelial cells (HUVECs) in a dose and time‐dependent manner. Both beclin‐1 small interfering RNA and 3‐methyladenine treatment predominantly mitigated VEGF‐A‐induced tube formation and migration of HUVECs, but they failed to elicit any notable effect on VEGF‐A‐increased expression of GRP78/Bip. Tauroursodeoxycholic acid not only obviously abolished VEGF‐A‐induced increase of IRE‐1, GRP78/Bip, beclin‐1 expression, and LC3‐II/LC3‐I, but also negated VEGF‐A‐induced tube formation and migration of HUVECs. Furthermore, N‐acetyl‐ l‐cysteine markedly abrogated VEGF‐A‐increased ROS production, IRE‐1, GRP78/Bip, beclin‐1 expression, and LC3‐II/LC3‐I in the HUVECs. Taken together, our data demonstrated that increased spontaneous production of VEGF‐A may induce angiogenesis after AMI through initiating ROS–ER stress‐autophagy axis in the vascular endothelial cells.

Role of Muscle-Specific Histone Methyltransferase (Smyd1) in Exercise-Induced Cardioprotection against Pathological Remodeling after Myocardial Infarction

“…Moderate ROS also upregulated Trx1 and Smyd1 in H9C2 cells, similar to what we found in intact hearts following exercise training. Despite excessive oxidative stress after MI being a contributing factor for cardiac remodeling [ 3 , 40 ], due to its action to increase cell permeability and trigger cell injury signaling pathways [ 41 ], ROS may also induce cardiac angiogenesis [ 58 ] and cardioprotection [ 59 , 60 ] in a dose-dependent manner. Indeed, here, we found that 50-200 µmol/L H 2 O 2 increased Trx1 expression and 300 µmol/L H 2 O 2 led to cell death.…”

Keap1‐Nrf2 signaling pathway in angiogenesis and vascular diseases

“…In summary, appropriate amounts of ROS were shown to be proangiogenic factors through various mechanisms, including enhancing VEGF and angiopoietin‐1/Tie‐2 signaling (Harel et al, 2017; Zou et al, 2019). Besides, Nrf2 pathway played a direct or indirect positive role in regulating angiogenesis under oxidative stress.…”

The Effect of YiQiFuMai on Ischemic Heart Failure by Improve Myocardial Microcirculation and Increase eNOS and VEGF Expression

“…This process may be mediated by activated PI3K/AKT/ Hif-1α pathway [22]. Zou et al also demonstrated that upregulation of VEGF in the rat model of acute myocardial infarction stimulates ROS production, which in turn induces oxidative stress in the endoplasmic reticulum, as well as autophagy, thereby promoting cardiac neovascularization [23]. This study revealed that VEGF protein amounts were increased after treatment with YiQiFuMai.…”