Zhang, Bin

Perivascular adipose tissue releases inflammatory paracrine factors that accelerate development of vascular dysfunction, atherosclerosis, and large vessel diseases such as abdominal aortic aneurysm. Our group has shown that chronic hypercholesterolemia and chronological aging both significantly increase senescent cell burden in vascular and endothelial cell populations of large arteries, but the effects of chronic hypercholesterolemia on senescent cell burden in perivascular adipose tissue—as well as the biological impact of reducing those senescent cells using pharmacological or genetic interventions—is poorly understood. Here, we sought to investigate the effects of chronic, intermittent senescent cell clearance by treating mice with Fisetin—a flavenoid shown to be a potent senolytic in multiple tissue types—and its potential synergies with risk factor mitigation. In brief, “Reversa” mice (ldlr-deficient, apoB100-only mice in which lipids can be lowered with a genetic switch) were fed a Western diet for 6 months, at which point they were randomized to one of three groups for 2 additional months: 1) continued progression on Western Diet (WD), 2) risk factor mitigation/lipid lowering with a genetic switch (LL) or 3) weekly, intermittent treatment with Fisetin + lipid lowering (FIS+LL). Compared to WD mice, LL mice had modest reductions in perivascular adipose inflammatory markers such as IL-6, CCL2, and CD-68, as well as the pro-oxidant Nox2; however, LL mice experienced no impact on expression of the pro-inflammatory cytokine TNFalpha. Interestingly, while intermittent Fisetin treatment and lipid lowering in the FIS+LL group had a significant additive effect on reducing IL-6, Nox2, and CD68, these changes were associated with modest reductions in expression of p16 ink4a or p21 (both of which are markers of senescent cell burden). Collectively, these data suggest that Fisetin is likely to modestly reduce senescent cell burden in perivascular fat, while effectively synergizing with lipid lowering to reduce a subset of inflammatory markers in this tissue, which may ultimately have implications for management of multiple age-associated vascular diseases.

Endothelial cell senescence promotes inflammation and impairs endothelium-dependent vasodilation. While aging, hypercholesterolemia, and caloric excess are known to drive cellular senescence in part through activation of mTOR, it is unknown whether reducing mTOR signaling can improve vasomotor function in aging mice. Here, we used hypercholesterolemic mice (Ldlr -/- /apoB 100/100 , or LA) carrying intact copies of mTOR (LA-mTOR +/+ ) or were deficient in one copy of mTOR (LA- mTOR +/- ). Mice were fed Western Diet for 6 or 12 months, and vasomotor function in aorta was evaluated using isolated organ chamber baths. Maximum relaxation to acetylcholine (MR ACH ) was progressively impaired from 6 months to 12 months in LA-mTOR +/+ mice (55±4% and 30±4%, respectively). In contrast to our hypothesis, however, MR ACH was not significantly improved in LA-mTOR +/- mice at either time point (62±3% and 35±5%, respectively). Interestingly, a subgroup analysis showed significant improvement in MR ACH in male mice at the 6-month point (male LA-mTOR +/+ mice = 30 ± 9% vs male LA-mTOR +/- mice = 55±4%; p < 0.01), whereas vasomotor function in female mice was nearly identical across groups. There was no significant difference at the 12-month point (male LA-mTOR +/+ mice = 19 ± 3% vs male LA-mTOR +/- mice = 22 ± 5%). Relaxation to acetylcholine was attenuated by L-NAME at 6 months and 12 months (but identical between genotypes) and relaxation to nitroprusside was identical between strains at each time point, suggesting that changes in endothelial function were not masked by compensatory mechanisms (e.g., endothelium-derived hyperpolarizing factors). Furthermore, reduction of mTOR did not elicit changes in maximal tension generated in response to Prostaglandin F 2 α at either time point. Collectively, despite compelling evidence from in vitro model systems, genetic reduction of mTOR signaling in vivo does not appear to be sufficient to improve vasomotor function in our model of aging hypercholesterolemic mice. Our data do, however, shed light on a potential role of sex in dictating phenotypic changes in early to moderate stages of disease, which warrants further investigation.

OBJECTIVEAlthough intracranial arterial aneurysms (IAAs) of childhood are usually idiopathic, it is possible that underlying arteriopathy escapes detection when using conventional diagnostic tools. Quantitative arterial tortuosity (QAT) has been studied as a biomarker of arteriopathy. The authors analyzed cervicocerebral QAT in children with idiopathic IAAs to assess the possibility of arteriopathy.METHODSCases were identified by text-string searches of imaging reports spanning the period January 1993 through June 2017. QAT of cervicocerebral arterial segments was measured from cross-sectional studies using image-processing software. Other imaging and clinical data were confirmed by retrospective electronic record review. Children with idiopathic IAAs and positive case controls, with congenital arteriopathy differentiated according to aneurysm status (with and without an aneurysm), were compared to each other and to healthy controls without vascular risk factors.RESULTSCervicocerebral QAT was measured in 314 children: 24 with idiopathic IAAs, 163 with congenital arteriopathy (including 14 arteriopathic IAAs), and 127 healthy controls. QAT of all vertebrobasilar segments was larger in children with IAAs (idiopathic and arteriopathic forms) (p < 0.05). In children with congenital arteriopathy without an aneurysm, QAT was decreased for the distal cervical vertebral arteries and increased for the supraspinal vertebral artery relative to healthy children. QAT of specific cervicocerebral segments correlated with IAA size and rupture status.CONCLUSIONSCervicocerebral QAT is a biomarker of arteriopathy in children with IAA, even in the absence of other disease markers. Additional findings suggest a correlation of cervicocerebral QAT with IAA size and rupture status and with the presence of IAA in children with congenital arteriopathy.