The Microenvironment That Regulates Vascular Wall Stem/Progenitor Cells in Vascular Injury and Repair

Abstract

Vascular repair upon injury is a frequently encountered pathology in cardiovascular diseases, which is crucial for the maintenance of arterial homeostasis and function. Stem/progenitor cells located on vascular walls have multidirectional differentiation potential and regenerative ability. It has been demonstrated that stem/progenitor cells play an essential role in the basic medical research and disease treatment. The dynamic microenvironment around the vascular wall stem/progenitor cells (VW-S/PCs) possesses many stem cell niche-like characteristics to support and regulate cells' activities, maintaining the properties of stem cells. Under physiological conditions, vascular homeostasis is a cautiously balanced and efficient interaction between stem cells and the microenvironment. These interactions contribute to the vascular repair and remodeling upon vessel injury. However, the signaling mechanisms involved in the regulation of microenvironment on stem cells remain to be further elucidated. Understanding the functional characteristics and potential mechanisms of VW-S/PCs is of great significance for both basic and translational research. This review underscores the microenvironment-derived signals that regulate VW-S/PCs and aims at providing new targets for the treatment of related cardiovascular diseases.

Figure 1

Proposed model of microenvironment in vascular stem cells niche. The vessel wall comprises an inner layer (intima), a thicker media layer (smooth muscle cells), and an outer layer (adventitia). The intima is mainly composed of a monolayer of endothelial cells (ECs), including mature and terminally differentiated cells (pink) and also endothelial progenitor cells (EPCs) (blue), which can proliferate, migrate, and differentiate into ECs to replace injured ECs in vascular repair. The adventitia is a dynamic layer in active communication with the other vessel wall layers, and it contains various cell types among others, including PCs (CD34⁺/SCa-1⁺ progenitor cells), mesenchymal stem cells (MSCs), macrophages, fibroblasts, adipocytes, pericytes, lymphocytes (B cells and T cells), and NK cells surrounding the neural fibers, lymphatic vessels, and secreted signaling molecules in adventitia.

Figure 2

Multiple signaling pathways are involved in the migration of VW-S/PCs. Under physiological conditions, VW-S/PCs reside in the microenvironment “stem cell niche.” In vascular diseases, inflammatory factors, cytokines, and chemokines are released by activated VW-S/PCs. IL-10 affects intracellular expression of related genes through JAK-STAT pathway, and SOCS is a specific inhibitor of the pathway. Vascular Sca-1⁺ cell migration can be induced by SMC-derived chemokine CCR2 and CXCR2 through the CCR2/Rac1/P38 and CXCR2/Rac1/P38 signaling pathways. Extracellular matrix (ECM) induces phenotypic transformation and cytoskeletal changes and affects the intracellular pH balance, providing a potential target for vascular diseases.