Matrix stiffness regulates endothelial cell proliferation through septin 9.

Area of Science:

• Biomaterials Science
• Cell Biology
• Vascular Biology

Background:

• Endothelial cell (EC) proliferation is crucial for vascular homeostasis.
• The extracellular microenvironment, particularly matrix stiffness, influences EC behavior.
• Understanding mechanical regulation of ECs is vital for tissue engineering and disease treatment.

Purpose of the Study:

• To investigate the molecular mechanisms underlying the mechanical regulation of endothelial cell proliferation.
• To elucidate the role of the SEPT9/Src/Vav2/RhoA pathway in response to matrix stiffness.

Main Methods:

• Culturing endothelial cells on hydrogels of varying stiffness (1.72 kPa vs. 21.5 kPa).
• Assessing cell proliferation, stress fiber formation, and RhoA activity.
• Utilizing pharmacological inhibitors and gene silencing for key pathway components (RhoA, Src, Vav2, SEPT9, integrin α(v)β(3)).

Main Results:

• High stiffness hydrogels (HSG) enhanced EC proliferation, stress fiber formation, and RhoA activity compared to low stiffness hydrogels (LSG).
• The SEPT9/Src/Vav2/RhoA pathway mediated stiffness-dependent EC proliferation.
• Integrin α(v)β(3) inactivation on HSG increased SEPT9, inhibiting the proliferation pathway.

Conclusions:

• The SEPT9/Src/Vav2/RhoA signaling cascade is a key molecular mechanism for mechanical control of EC proliferation.
• Matrix stiffness dictates EC proliferation through this pathway, offering potential therapeutic targets.