Perivascular cells function as key mediators of mechanical and structural changes in vascular capillaries

Area of Science:

• Biomedical Engineering
• Vascular Biology
• Extracellular Matrix Research

Background:

• Chronic and inflammatory diseases feature fibrotic, stiff extracellular matrix (ECM) and abnormal microvascular capillaries.
• Mechanisms linking ECM alterations to microvascular responses are largely unknown.
• Perivascular cells are crucial for vascular integrity and function.

Purpose of the Study:

• To investigate the role of perivascular cells in mediating vascular capillary responses to altered ECM.
• To elucidate the signaling pathways involved in endothelial-perivascular cell communication under fibrotic conditions.
• To understand the contribution of NOTCH3 signaling in vascular adaptation to ECM changes.

Main Methods:

• Utilized a microphysiological 'capillaries on a chip' model.
• Engineered capillaries within healthy or fibrotic collagen matrices.
• Assessed perivascular cell migration, pericyte differentiation, vascular leakage, and gene expression.
• Investigated the role of NOTCH3 signaling by silencing its expression in perivascular cells.

Main Results:

• Capillaries in fibrotic ECM exhibited abnormal perivascular cell migration and reduced pericyte differentiation.
• Increased vascular leakage and upregulation of inflammatory/remodeling genes were observed in fibrotic conditions.
• NOTCH3 signaling was identified as a key regulator of these responses, mediating endothelial-perivascular cell communication.
• Endothelial cells alone or perivascular cells with silenced NOTCH3 showed minimal response to ECM alterations.

Conclusions:

• Perivascular cells, through NOTCH3 signaling, are critical mediators of vascular capillary responses to ECM fibrosis.
• This study reveals a novel mechanism for vascular dysfunction in fibrotic diseases.
• Findings highlight NOTCH3 as a potential therapeutic target for managing vascular complications in chronic inflammatory diseases.