Loss of the serine protease HTRA1 impairs smooth muscle cells maturation
| Autor: | Andreas Fischer, Thomas Korff, Juan Rodriguez-Vita, Fabian Tetzlaff, Ralph Klose, Chio Oka, Eva-Maria Weis, Iris Moll, Alexander Prinz |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
JAG1 Vascular smooth muscle Blotting Western Cell Notch signaling pathway Fluorescent Antibody Technique lcsh:Medicine Real-Time Polymerase Chain Reaction Article Muscle Smooth Vascular Mice 03 medical and health sciences 0302 clinical medicine Transforming Growth Factor beta medicine Animals Humans lcsh:Science Receptor Notch3 Mice Knockout Multidisciplinary Molecular medicine Chemistry lcsh:R Serine Protease HTRA1 High-Temperature Requirement A Serine Peptidase 1 Phenotype eye diseases Cell biology Mice Inbred C57BL Cardiovascular diseases 030104 developmental biology medicine.anatomical_structure HTRA1 cardiovascular system lcsh:Q 030217 neurology & neurosurgery Homeostasis Muscle Contraction Signal Transduction |
| Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-10 (2019) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-54807-6 |
| Popis: | Vascular smooth muscle cell (VSMC) dysfunction is a hallmark of small vessel disease, a common cause of stroke and dementia. Two of the most frequently mutated genes in familial small vessel disease are HTRA1 and NOTCH3. The protease HTRA1 cleaves the NOTCH3 ligand JAG1 implying a mechanistic link between HTRA1 and Notch signaling. Here we report that HTRA1 is essential for VSMC differentiation into the contractile phenotype. Mechanistically, loss of HTRA1 increased JAG1 protein levels and NOTCH3 signaling activity in VSMC. In addition, the loss of HTRA1 enhanced TGFβ-SMAD2/3 signaling activity. Activation of either NOTCH3 or TGFβ signaling resulted in increased transcription of the HES and HEY transcriptional repressors and promoted the contractile VSMC phenotype. However, their combined over-activation led to an additive accumulation of HES and HEY proteins, which repressed the expression of contractile VSMC marker genes. As a result, VSMC adopted an immature phenotype with impaired arterial vasoconstriction in Htra1-deficient mice. These data demonstrate an essential role of HTRA1 in vascular maturation and homeostasis by controlling Notch and TGFβ signaling. |
| Databáze: | OpenAIRE |
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