Henson, G. D. | Search bioRxiv

bioRxiv2025

Cerebral blood flow in elastin haploinsufficient and 3xTg-AD mice

Artery structural properties and Alzheimers disease (AD) pathology are individually associated with impaired cerebrovascular function; however, the interaction of these factors is unclear. Furthermore, while elastin haploinsufficient (Eln+/-) mice are known to have impaired cerebrovascular function, sex differences for this effect have not been previously studied. To answer these questions, we crossed middle-aged and old Eln+/-mice with 3xTg-AD mice. We measured cerebral blood flow (CBF) using arterial spin labeling MRI at rest and during hypercapnia to calculate cerebrovascular reactivity (CVR). We also assessed neuroinflammation by microglia and astrocyte cell counts. We found that Eln+/- mice had lower resting blood flow rate in the cerebral cortex compared with Eln+/+ mice, but Eln+/- mice had an intact hypercapnic response, resulting in better CVR compared with Eln+/+ in hippocampus. Sex did not impact resting blood flow or CVR. 3xTg-AD mice had a lower resting CBF than non-AD mice, and there was an interaction between Eln genotype and AD mutations on CVR, such that Eln+/-x 3xTg-AD mice had the poorest hippocampal CVR of all groups. Glia cell counts were highly dependent on brain region, with Eln+/- having more microglia but fewer astrocytes, while 3xTg-AD having higher both microglia and astrocytes. While sex also impacted glial cell counts, we found no interactions between sex and Eln genotype. Our results demonstrate that elastin haploinsufficiency and AD mutations individually result in lower resting CBF, and the combination of these leads to impaired CVR. NEW & NOTEWORTHYThe findings of this study demonstrate that elastin haploinsufficiency leads to lower resting cerebral blood flow, but also greater cerebrovascular reactivity. However, elastin haploinsufficiency interacts with Alzheimers disease mutations to impair cerebrovascular reactivity. These results suggest that multiple insults, such as changes to the extracellular matrix combined with genetic risk factors, are needed to impact cerebrovascular reactivity.

physiology↗

bioRxiv2020

Sirt1 overexpression attenuates high-fat diet induced aortic stiffening

Increased arterial stiffness is a cardiovascular disease risk factor in the setting of advancing age and high-fat (HF) diet induced obesity. Increases in large artery stiffness, as measured by pulse wave velocity (PWV), occur within 8 weeks of HF feeding in mice. Sirtuin-1 (Sirt1), a NAD-dependent deacetylase, regulates cellular metabolic activity and activation of this protein has been associated with vasoprotection in aged mice. The aim of the present study was to elucidate the effect of global Sirt1 overexpression (Sirttg) on HF diet-induced arterial stiffening. Sirt1 overexpression did not influence PWV in normal chow (NC) fed mice (Sirttg: 263 {+/-} 6 vs WT: 274 {+/-} 7, p=0.28). However, PWV was higher in wild-type (WT) mice (376 {+/-} 22, p<0.04), but not Sirttg (304 {+/-} 2 cm/s, p=0.07), after 12 weeks of HF diet. Despite no effect of Sirt1 overexpression on aortic collagen content in NC (p=0.71), aortic elastin content was higher in Sirttg mice compared with WT mice fed NC diet (P<0.05). Surprisingly, despite increased arterial stiffness, collagen content was lower (p<0.02) and elastin content was unchanged (p=0.05) in the aortas of WT mice after HF. Neither collagen (p=0.18) nor elastin content (p=0.56) were impacted by HF diet in the Sirttg mice. Likewise, there was no difference in wall thickness in NC (Sirttg: 40.7 {+/-} 2 vs WT: 41.6 {+/-} 2, p= 0.78). However, wall thickness was higher in mice WT mice fed a HF diet (51.7 {+/-} 2, p<0.01) and there was no difference in Sirttg mice after HF diet (p=0.66). Similarly, there was no difference in wall-to-lumen ratio in mice fed NC diet (Sirttg: 0.08 vs WT: 0.08, p=0.48) was higher in HF diet fed WT mice (p<0.01), though, HF diet was associated with a higher wall-to-lumen ratio in WT (0.11, p<0.01), but not different in Sirttg mice fed HF diet (0.08, p=0.59). These findings demonstrate a vasoprotective effect of Sirt1 overexpression that limits increases in arterial stiffness and protects against alterations in vessel morphology in response to HF feeding. As such, activation of Sirt1 may be a novel therapeutic target to prevent elevated CVD risk associated with HF-induced aortic stiffening.

physiology↗