Article Impact Level: HIGH Data Quality: STRONG Summary of Journal of Biological Chemistry, 301(4), 108400. https://doi.org/10.1016/j.jbc.2025.108400 Dr. Catarina Rippe et al.
Points
- Researchers observed that in aging human arteries, the gene expression controller Serum Response Factor (SRF) and its related structural proteins decline, contributing to age-related vascular weakening.
- To mimic this process, scientists genetically removed the SRF protein in young mice, which, as expected, caused impaired arterial contractility and early signs of aortic aneurysm formation.
- Surprisingly, these same mice were protected from severe aortic damage when challenged with hypertension, indicating that SRF depletion also activated an unexpected and powerful compensatory protective mechanism.
- The study revealed that this protection occurs because SRF reduction leads to a decrease in the Lats2 kinase, which in turn unleashes the activity of the protective proteins YAP/TAZ.
- These findings suggest that developing drugs to inhibit the Lats2 kinase specifically could become a novel therapeutic strategy to protect blood vessels from the damage caused by hypertension.
Summary
A study investigating the molecular basis of age-related arterial disease identified a key transcriptional shift in the human aorta. RNA-sequencing of aged human arteries revealed significant repression of transcripts essential for actomyosin structure, including myosin light chain kinase (MYLK) and smooth muscle γ-actin (ACTG2). This change was linked to a corresponding reduction in their controlling transcription factor, serum response factor (SRF). To model this, researchers developed mice with conditional SRF deletion in vascular smooth muscle (i8-SRF-KO). These mice exhibited a phenotype mimicking arterial aging, with reduced Mylk and Actg2 expression, impaired arterial contractility, increased aortic diameter, and positive Alcian blue staining of the aortic media, indicating early aortopathy.
Despite these pro-aneurysmal changes, i8-SRF-KO mice were unexpectedly protected from aortic lesions typically induced by angiotensin II (AngII). Proteomic analysis uncovered the compensatory mechanism: SRF depletion resulted in a marked decrease in the Hippo kinase Lats2, which in turn led to the activation of the mechanoresponsive transcriptional coactivators YAP and TAZ. This SRF-Lats2-YAP/TAZ signaling axis appears to be a critical adaptive pathway. The strength of this relationship was highlighted by the finding that activating SRF expression led to a nearly 200-fold increase in Lats2.
The protective role of this compensatory pathway was further validated by experiments altering the sequence of interventions. When AngII administration preceded the induction of SRF knockout, the protective effect was nullified, resulting in advanced aneurysmal disease in both i8-SRF-KO and control mice. These findings elucidate a novel mechanism through which the aging aorta adapts to biomechanical stress. The data suggest that targeted pharmacological inhibition of the specific Lats2 isoform present in the vascular wall could represent a future therapeutic strategy to protect against vascular damage in hypertension.
Link to the article: https://www.jbc.org/article/S0021-9258(25)00249-2/fulltext
References Rippe, C., Bastrup, J. A., Holmberg, J., Kawka, K., Arévalo Martinez, M., Albinsson, S., Jepps, T. A., & Swärd, K. (2025). Declining activity of serum response factor in aging aorta in relation to aneurysm progression. Journal of Biological Chemistry, 301(4), 108400. https://doi.org/10.1016/j.jbc.2025.108400
