Molecular mechanisms of endothelial-mesenchymal transition and its pathophysiological feature in cerebrovascular disease

Abstract

The phenomenon of endothelial-mesenchymal transition (EndMT), a distinct subtype of epithelial-mesenchymal transition (EMT), has garnered significant attention from scholars. EndMT refers to the process whereby endothelial cells (ECs) transform into mesenchymal cells in response to various stimuli, resulting in the loss of their original characteristics. This process has diverse implications in both physiological and pathological states. Under physiological conditions, EndMT plays a crucial role in the development of the cardiovascular system. Conversely, under pathological conditions, EndMT has been identified as a pivotal factor in the development of cardiovascular diseases. Nonetheless, a comprehensive overview of EndMT in cerebrovascular disease is currently lacking. Here, we discuss the heterogeneity of EndMT occurrence and the regulatory factors involved in its development and analyze the feasibility of EndMT as a therapeutic target, aiming to provide a solid theoretical foundation and evidence to address diseases caused by pathological EndMT.

Keywords: Cerebrovascular disease; EndMT; Endothelial cells; Vascular remodeling.

Fig. 1

Different types of EndMT. The first type of EndMT is the direct transdifferentiation of ECs into fibroblasts, myofibroblasts, and SMCs, among other types of cells. Second, ECs lose their properties and transform into MSCs, which in turn differentiate into a variety of cell types, such as mature mesenchymal cells, fibroblasts, myofibroblasts, SMCs, adipocytes, osteoblasts, and chondrocytes. The third type consists of EPCs that can be transdifferentiated into mesenchymal cells under specific conditions and then undergo transformation similar to the second type. The fourth type consists of tumor ECs specific to the tumor tissue and can be transdifferentiated into stem cell-like cells and then into cancer-associated fibroblasts (CAFs) and myofibroblasts

Fig. 2

ECs initiate EndMT by loosening ECs junctions under multiple factors. TGF-β, inflammatory factors, and other stimuli initiate EndMT in ECs. In the initiation phase, EC junctions loosen, enabling cell migration to specific sites. The mesenchymal transition phase can occur in two forms: a transitional phase in which cells exhibit both endothelial and mesenchymal characteristics and another where cells fully acquire mesenchymal cell characteristics

Fig. 3

A schematic illustration of the signaling pathways governing EndMT. Various mechanisms regulate EndMT, the classic pathway is the TGF-β pathway, which regulates EndMT through Smad2/3 and transcription factors such as Snail and ZEB1. Multiple stimuli, including hypoxia, low shear, miRNA21, and inflammatory factors such as IL-1β and TNF-α, can act on TGF-β or act synergistically to promote EndMT. BMP7 inhibits EndMT by inhibiting TGF-β or AKT/mTOR. Some miRNAs exert inhibitory effects on EndMT