Loss of the serine protease HTRA1 impairs smooth muscle cells maturation

Area of Science:

• Vascular biology
• Cell signaling
• Genetics

Background:

• Vascular smooth muscle cell (VSMC) dysfunction is central to small vessel disease, a cause of stroke and dementia.
• Mutations in HTRA1 and NOTCH3 are common in familial small vessel disease.
• HTRA1 protease activity on JAG1 suggests a link between HTRA1 and Notch signaling.

Purpose of the Study:

• To investigate the role of HTRA1 in VSMC differentiation and function.
• To elucidate the molecular mechanisms by which HTRA1 influences vascular homeostasis.
• To determine the interplay between HTRA1, Notch, and TGFβ signaling in VSMCs.

Main Methods:

• Analysis of HTRA1's role in VSMC differentiation.
• Assessment of JAG1 protein levels and NOTCH3 signaling activity in VSMCs.
• Evaluation of TGFβ-SMAD2/3 signaling pathway activation.
• Investigation of HES/HEY transcriptional repressor activity.
• Phenotypic analysis of Htra1-deficient mice, including arterial vasoconstriction.

Main Results:

• HTRA1 is essential for VSMC differentiation into the contractile phenotype.
• Loss of HTRA1 increases JAG1 protein, NOTCH3, and TGFβ signaling.
• Over-activation of NOTCH3 and TGFβ signaling leads to HES/HEY accumulation and repression of contractile markers.
• Htra1-deficient mice exhibit immature VSMCs and impaired arterial vasoconstriction.

Conclusions:

• HTRA1 plays a critical role in vascular maturation and homeostasis.
• HTRA1 regulates VSMC phenotype by controlling Notch and TGFβ signaling pathways.
• Dysregulation of HTRA1 contributes to small vessel disease pathogenesis.