Mining the Stiffness-Sensitive Transcriptome in Human Vascular Smooth Muscle Cells Identifies Long Noncoding RNA...

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Genomics

Background:

• Vascular extracellular matrix stiffening is a significant risk factor for aortic and coronary artery disease.
• The impact of matrix stiffening on the transcriptome of vascular smooth muscle cells (VSMCs) is not fully understood.
• The role of long noncoding RNAs (lncRNAs) in VSMC response to matrix stiffness remains unexplored.

Purpose of the Study:

• To characterize the stiffness-sensitive (SS) transcriptome of human aortic and coronary VSMCs.
• To identify potential lncRNA regulators of stiffness-dependent VSMC functions.

Main Methods:

• Human aortic and coronary VSMCs were cultured on hydrogel substrates simulating physiological and pathological matrix stiffness.
• Total RNA sequencing (RNAseq) was employed to compare SS transcriptome profiles.
• Unbiased systems analyses were used to identify key lncRNA regulators.

Main Results:

• 3098 stiffness-sensitive genes, including 157 lncRNAs, were identified in both aortic and coronary VSMCs.
• VSMCs clustered by stiffness rather than cell origin, indicating stiffness as a primary determinant of gene expression.
• MALAT1 was identified as a stiffness-sensitive lncRNA regulating VSMC proliferation and migration in vitro and in vivo.

Conclusions:

• This study presents the transcriptomic landscape of human VSMCs in response to matrix stiffness, identifying novel SS human lncRNAs.
• The SS transcriptome is evolutionarily important for VSMC function.
• SS lncRNAs can function as critical regulators of stiffness-dependent VSMC phenotypes.