F Tosato(1), A Aronova(1), N Naser(1), SW. van der Laan(2), L Strom(3), C Behrends(3), S Steffens(4), C Weber(4), J Bernhagen(1), Y Asare(1), M Dichgans(1)

1: Institute for Stroke and Dementia Research, LMU Munich, Munich, Germany; 2: University Medical Center Utrecht, University of Utrecht, the Netherlands; 3: Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), LMU Munich, Munich, Germany; 4: Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

Variants at the HDAC9 locus associate with carotid intima-media thickness, a well-established parameter in arterial remodeling after vascular injury. The candidacy of HDAC9 as a target molecule in vascular repair processes after injury is supported by the recognized role of HDACs as regulators of inflammation and immunity but also cell proliferation, migration, and apoptosis in multiple cell types including vascular endothelial (ECs) and smooth muscle cells (SMCs). However, the functional role of HDAC9 in neointima formation is largely unexplored. 

By combining in vitro and in vivo vascular injury models, we demonstrated that Hdac9 deficiency attenuates neointima formation in carotid arteries upon arterial damage, with a reduction in total cells in the lesion, in particular of SMCs. In parallel, a reduction of endothelial Vcam-1 expression in Hdac9–/–Apoe–/– mice compared to control littermates was revealed by two-photon imaging of whole-mount carotid arteries. Since proliferation is pivotal in neointima formation, we examined the effect of HDAC9 on VSMC proliferation and found HDAC9 depletion to reduce PDGF-BB-induced proliferation of human aortic SMCs. This finding goes alongside with the reduction in Cyclin D1 expression. Interestingly, a decreased proliferation has also been observed in mouse aortic ECs upon Hdac9 inhibition. We further showed that HDAC9 promotes pro-inflammatory responses in primary ECs and VSMCs. Moreover, proteome profiling of Hdac9-depleted MAoECs resulted in a broad proinflammatory response, showing downregulation of the JNK pathway and in particular of the downstream transcription factor Atf2, thus implicating JNK-ATF2 axis as a new target of HDAC9 in EC.