Mechanical forces remodel the cardiac extracellular matrix during zebrafish development

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Biophysics

Background:

• The cardiac extracellular matrix (cECM) is crucial for heart development and maturation.
• The role of mechanical forces, like those from heartbeats, in regulating cECM remodeling during development is largely unknown.

Purpose of the Study:

• To investigate whether mechanical forces from cardiac contraction regulate cECM remodeling during zebrafish heart development.
• To identify molecular mechanisms, including specific ECM remodelers, involved in this process.

Main Methods:

• Utilized zebrafish as a model organism during cardiac valve and trabeculae formation.
• Performed longitudinal volumetric quantification of cECM.
• Manipulated cardiac contraction and heart rate.
• Conducted loss- and gain-of-function studies for tissue inhibitor of matrix metalloproteinase 2 (TIMP2).

Main Results:

• Altering cardiac contraction significantly impaired cECM remodeling.
• cECM volume dynamics were chamber-specific: decreasing in the atrium but not the ventricle or atrioventricular canal.
• Mechanical forces regulate cECM remodeling in a chamber-specific manner.
• TIMP2 was upregulated in non-contractile hearts and its modulation critically affected cECM remodeling.

Conclusions:

• Mechanical forces generated by the heartbeat play a significant role in regulating cECM remodeling during heart development.
• This regulation is chamber-specific and involves, in part, the downregulation of TIMP2.