Impact of arterial stiffness on cerebrovascular function: a review of evidence from humans and preclincal models.

With advancing age, the cerebral vasculature becomes dysfunctional, and this dysfunction is associated with cognitive decline. However, the initiating cause of these age-related cerebrovascular impairments remains incompletely understood. A characteristic feature of the aging vasculature is the increase in stiffness of the large elastic arteries. This increase in arterial stiffness is associated with elevated pulse pressure and blood flow pulsatility in the cerebral vasculature. Evidence from both humans and rodents supports that increases in large elastic artery stiffness are associated with cerebrovascular impairments. These impacts on cerebrovascular function are wide-ranging and include reductions in global and regional cerebral blood flow, cerebral small vessel disease, endothelial cell dysfunction, and impaired perivascular clearance. Furthermore, recent findings suggest that the relationship between arterial stiffness and cerebrovascular function may be influenced by genetics, specifically APOE and NOTCH genotypes. Given the strength of the evidence that age-related increases in arterial stiffness have deleterious impacts on the brain, interventions that target arterial stiffness are needed. The purpose of this review is to summarize the evidence from human and rodent studies, supporting the role of increased arterial stiffness in age-related cerebrovascular impairments.

Effects of dietary soy content on cerebral artery function and behavior in ovariectomized female mice.

As females age, they transition through menopause, experiencing a decrease in estrogen and an increase in cardiovascular and neurodegenerative disease risk. Most standard rodent chows contain phytoestrogen-rich soybean meal, which can mimic the effects of estrogen. Understanding the impact of this soybean meal on vascular outcomes is crucial to proper experimental design. Thus, this study aimed to compare the effects of standard and soy-free chows on cerebral artery endothelial function and cognitive function in ovariectomized mice. Young female C57Bl/6J mice (n = 43; ∼6 mo) were randomly assigned to three groups: sham, ovariectomy (OVX), or ovariectomy on a diet containing soy (OVX + Soy). In posterior cerebral arteries, the OVX mice had a 27% lower maximal response to insulin compared with the sham mice. The OVX + Soy mice had a 27% greater maximal vasodilation to insulin compared with the OVX mice and there were no differences in vasodilation between the OVX + Soy and sham groups. The group differences in vasodilation were mediated by differences in nitric oxide bioavailability. The OVX + Soy mice also had greater insulin receptor gene expression in cerebral arteries compared with the OVX mice. However, no differences in aortic or cerebral artery stiffness were observed between groups. Interestingly, the OVX + Soy group scored better on nesting behavior compared with both sham and OVX groups. In summary, we found that ovariectomy impairs insulin-mediated vasodilation in cerebral arteries, but a diet containing soy mitigates these effects. These findings highlight the importance of considering dietary soy when performing vascular and behavioral tests in mice, particularly in females.NEW & NOTEWORTHY To properly design experiments, we must consider how variables like diet impact our outcomes, particularly the effects of soy on females. We found that cerebral artery vasodilation in response to insulin was impaired in ovariectomized female mice compared with intact shams. However, ovariectomized mice fed a soy diet had a preserved cerebral artery insulin-mediated vasodilation. These results highlight that the effects of diet on vascular function may explain inconsistencies found between studies.

Heterozygosity for ADP-ribosylation factor 6 suppresses the burden and severity of atherosclerosis.

Atherosclerosis is the root cause of major cardiovascular diseases (CVD) such as myocardial infarction and stroke. ADP-ribosylation factor 6 (Arf6) is a ubiquitously expressed GTPase known to be involved in inflammation, vascular permeability and is sensitive to changes in shear stress. Here, using atheroprone, ApoE-/- mice, with a single allele deletion of Arf6 (HET) or wildtype Arf6 (WT), we demonstrate that reduction in Arf6 attenuates atherosclerotic plaque burden and severity. We found that plaque burden in the descending aorta was lower in HET compared to WT mice (p˂0.001) after the consumption of an atherogenic Paigen diet for 5 weeks. Likewise, luminal occlusion, necrotic core size, plaque grade, elastic lamina breaks, and matrix deposition were lower in the aortic root atheromas of HET compared to WT mice (all p≤0.05). We also induced advanced human-like complex atherosclerotic plaque in the left carotid artery using partial carotid ligation surgery and found that atheroma area, plaque grade, intimal necrosis, intraplaque hemorrhage, thrombosis, and calcification were lower in HET compared to WT mice (all p≤0.04). Our findings suggest that the atheroprotection afforded by Arf6 heterozygosity may result from reduced immune cell migration (all p≤0.005) as well as endothelial and vascular smooth muscle cell proliferation (both p≤0.001) but independent of changes in circulating lipids (all p≥0.40). These findings demonstrate a critical role for Arf6 in the development and severity of atherosclerosis and suggest that Arf6 inhibition can be explored as a novel therapeutic strategy for the treatment of atherosclerotic CVD.

Advancing age increases the size and severity of spontaneous atheromas in mouse models of atherosclerosis.

Using multiple mouse models, we explored the impact of aging on the size and severity of atherosclerotic lesions. In young, middle-aged and old apolipoprotein E knockout mice (ApoE-/-) fed an atherogenic diet (AD) for 3-8 weeks, plaque/atheroma formation in the descending aorta and aortic root, and atheroma development in the carotid in response to partial carotid ligation (PCL) were assessed. Total and LDL cholesterol, and triglycerides were higher in old compared to both other age groups, regardless of AD duration. Aortic plaque burden increased with AD duration in all ages. The size and plaque morphology grade of aortic root atheromas was higher with age; however, there was no effect of age on the size or severity of carotid atheromas after PCL. We additionally induced hyperlipidemia in young and old C57BL/6 mice by adeno-associated virus mediated upregulation of LDL receptor regulator, Pcsk9, and 5 weeks of AD. Despite lower cholesterol in old compared to young Pcsk9 mice, there was a greater size and severity of aortic root atheromas in old mice. However, like the ApoE-/- mice, there was no effect of age on size or severity of PCL-induced carotid artery atheromas in Pcsk9 mice. Together, these results suggest that aging increases the size and severity of spontaneous aortic atheromas.

INFLUENCE OF OBESITY ON VASCULAR DYSFUNCTION AFTER TRAUMATIC HEMORRHAGE.

ABSTRACT: Background: Obesity increases the risk for morbidity and mortality after trauma. These complications are associated with profound vascular damage. Traumatic hemorrhage acutely attenuates vascular responsiveness, but the impact of obesity on this dysfunction is not known. The local inflammatory response in vascular cells is also unknown. We hypothesized that obesity potentiates trauma-induced vascular inflammation and dysfunction. Methods: Male Sprague-Dawley rats (~250 g) were fed normal chow (NC; 13.5% kcal fat, n = 20) or high-fat (HF; 60% kcal fat, n = 20) diets for 6 to 8 weeks. Under anesthesia, hemorrhage was induced by a mesenteric artery laceration, a Grade V splenic injury, and hypotension (MAP = 30-40 mm Hg) for 30 minutes. Vascular responsiveness was assessed ex vivo in isolated mesenteric arteries prehemorrhage and posthemorrhage. Gene expression for IL-1ß, and IL-6, prooxidant nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), and α-adrenergic receptor were assessed in carotid artery endothelial cells (ECs) and non-ECs (media + adventitia). Results: In NC rats, hemorrhage attenuated norepinephrine-induced vasoconstriction and endothelium-dependent vasodilation to acetylcholine. In HF rats, baseline norepinephrine-induced vasoconstriction was attenuated compared with NC, but vasoconstriction and endothelium-dependent vasodilation did not change prehemorrhage to posthemorrhage. Hemorrhage led to elevated IL-1ß gene expression in ECs and elevated IL1ß, IL-6, NOX2, and α-adrenergic receptor gene expression in the media + adventitia compared with sham. HF rats had greater EC IL-1 ß and NOX2 gene expression compared with NC rats. The hemorrhage-induced elevation of IL-1ß in the media + adventitia was greatest in HF rats. Conclusion: Traumatic hemorrhage attenuates vascular responsiveness and induces vascular inflammation. The attenuated vascular responsiveness after hemorrhage is absent in obese rats, while the elevated vascular inflammation persists. A HF diet amplifies the arterial inflammation after hemorrhage. Altered vascular responsiveness and vascular inflammation may contribute to worse outcomes in obese trauma patients.

High pulse pressure impairs cerebral artery endothelial function in young, but not old, mice.

One of the hallmarks of vascular aging is increased pulse pressure. This elevated pulse pressure is associated with deleterious effects on cerebral vascular function; however, it is unknown if age modulates the susceptibility to high pulse pressure. To examine the effects of age on the cerebral artery response to pulse pressure, we studied isolated cerebral arteries collected from young (6.1 ± 0.2 mo) and old (26.7 ± 0.5 mo) male C57BL/6 mice. Isolated cerebral arteries were exposed ex vivo to static pressure, low pulse pressure (25 mmHg), and high pulse pressure (50 mmHg). In cerebral arteries from young mice, endothelium-dependent dilation was similar between the static and low pulse pressure conditions. Exposure to high pulse pressure impaired endothelium-dependent dilation in cerebral arteries from young mice, mediated by less nitric oxide bioavailability and greater oxidative stress. Cerebral arteries from old mice had impaired cerebral artery endothelium-dependent dilation at static pressure compared with young cerebral arteries. However, exposure to low or high pulse pressure did not cause any further impairments to endothelium-dependent dilation in old cerebral arteries compared with static pressure. The old cerebral arteries had less distension during exposure to high pulse pressure and greater stiffness compared with young cerebral arteries. These results indicate that acute exposure to high pulse pressure impairs endothelium-dependent dilation in young, but not old, cerebral arteries. The greater stiffness of cerebral arteries from old mice potentially protects against the negative consequences of high pulse pressure.

Pyridoxamine treatment ameliorates large artery stiffening and cerebral artery endothelial dysfunction in old mice.

Age-related increases in large artery stiffness are associated with cerebrovascular dysfunction and cognitive impairment. Pyridoxamine treatment prevents large artery stiffening with advancing age, but the effects of pyridoxamine treatment on the cerebral vasculature or cognition is unknown. The purpose of this study was to investigate the effects of pyridoxamine on blood pressure, large artery stiffness, cerebral artery function, and cognitive function in old mice. Old male C57BL/6 mice consumed either pyridoxamine (2 g/L) or vehicle control in drinking water for ∼7.5 months and were compared with young male C57BL/6 mice. From pre- to post-treatment, systolic blood pressure increased in old control mice, but was maintained in pyridoxamine treated mice. Large artery stiffness decreased in pyridoxamine-treated mice but was unaffected in control mice. Pyridoxamine-treated mice had greater cerebral artery endothelium-dependent dilation compared with old control mice, and not different from young mice. Old control mice had impaired cognitive function; however, pyridoxamine only partially preserved cognitive function in old mice. In summary, pyridoxamine treatment in old mice prevented age-related increases in blood pressure, reduced large artery stiffness, preserved cerebral artery endothelial function, and partially preserved cognitive function. Taken together, these results suggest that pyridoxamine treatment may limit vascular aging.

In vivo arterial stiffness, but not isolated artery endothelial function, varies with the mouse estrous cycle.

With the increasing appreciation for sex as a biological variable and the inclusion of female mice in research, it is important to understand the influence of the estrous cycle on physiological function. Sex hormones are known to modulate vascular function, but the effects of the mouse estrous cycle phase on arterial stiffness, endothelial function, and arterial estrogen receptor expression remain unknown. In 23 female C57BL/6 mice (6 mo of age), we determined the estrous cycle stage via vaginal cytology and plasma hormone concentrations. Aortic stiffness, assessed by pulse wave velocity, was lower during the estrus phase compared with diestrus. In ex vivo assessment of isolated pressurized mesenteric and posterior cerebral arteries, the responses to acetylcholine, insulin, and sodium nitroprusside, as well as nitric oxide-mediated dilation, were not different between estrous cycle phases. In the aorta, expression of phosphorylated estrogen receptor-α was higher for mice in estrus compared with mice in proestrus. In the cerebral arteries, gene expression for estrogen receptor-ß (Esr2) was lowest for mice in estrus compared with diestrus and proestrus. These results demonstrate that the estrus phase is associated with lower in vivo large artery stiffness in mice. In contrast, ex vivo resistance artery endothelial function is not different between estrous cycle phases. Estrogen receptor expression is modulated by the estrus cycle in an artery-dependent manner. These results suggest that the estrous cycle phase should be considered when measuring in vivo arterial stiffness in young female mice.NEW & NOTEWORTHY To design rigorous vascular research studies using young female rodents, the influence of the estrous cycle on vascular function must be known. We found that in vivo aortic stiffness was lower during estrus compared with the diestrus phase in female mice. In contrast, ex vivo mesenteric and cerebral artery endothelial function did not differ between estrous cycle stages. These results suggest that the estrous cycle stage should be accounted for when measuring in vivo arterial stiffness.

Sex Differences in the Relation Between Frailty and Endothelial Dysfunction in Old Mice.

Vascular endothelial function declines with age on average, but there is high variability in the magnitude of this decline within populations. Measurements of frailty, known as frailty index (FI), can be used as surrogates for biological age, but it is unknown if frailty relates to the age-related decline in vascular function. To examine this relation, we studied young (4-9 months) and old (23-32 months) C57BL6 mice of both sexes. We found that FI was greater in old compared with young mice, but did not differ between old male and female mice. Middle cerebral artery (MCA) and mesenteric artery endothelium-dependent dilation (EDD) also did not differ between old male and female mice; however, there were sex differences in the relations between FI and EDD. For the MCA, FI was inversely related to EDD among old female mice, but not old male mice. In contrast, for the mesenteric artery, FI was inversely related to EDD among old male mice, but not old female mice. A higher FI was related to a greater improvement in EDD with the superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl in the MCAs for old female mice and in the mesenteric arteries for old male mice. FI related to mesenteric artery gene expression negatively for extracellular superoxide dismutase (Sod3) and positively for interleukin-1ß (Il1b). In summary, we found that the relation between frailty and endothelial function is dependent on sex and the artery examined. Arterial oxidative stress and proinflammatory signaling are potential mediators of the relations of frailty and endothelial function.

Neuroscience Education: Making It Relevant to Psychiatric Training.

Psychiatric education has struggled to move past dualistic notions separating mind from brain, and embrace the field's identity as a clinical neuroscience discipline. To modernize our educational systems, we must integrate neuroscience perspectives into every facet of our clinical work. To do this effectively, neuroscience education should be clinically relevant, informed by adult learning theory, and tailored to the individualized needs of learners. Classic neuropsychiatry skills can help us better understand our patients' brain function at the bedside. Integrating neuroscience perspectives alongside the other rich perspectives in psychiatry will help trainees appreciate the relevance of neuroscience to modern medical practice.

Sex Differences in Large Artery Stiffness: Implications for Cerebrovascular Dysfunction and Alzheimer's Disease.

Two in every three Alzheimer's disease diagnoses are females, calling attention to the need to understand sexual dimorphisms with aging and neurodegenerative disease progression. Dysfunction and damage to the vasculature with aging are strongly linked to Alzheimer's disease. With aging there is an increase in stiffness of the large elastic arteries, and this stiffening is associated with cerebrovascular dysfunction and cognitive impairment. However, it is unclear how the deleterious effects of arterial stiffness may differ between females and males. While environmental, chromosomal, and sex hormone factors influence aging, there is evidence that the deficiency of estrogen post-menopause in females is a contributor to vascular aging and Alzheimer's disease progression. The purpose of this mini review is to describe the recent developments in our understanding of sex differences in large artery stiffness, cerebrovascular dysfunction, and cognitive impairment, and their intricate relations. Furthermore, we will focus on the impact of the loss of estrogen post-menopause as a potential driving factor for these outcomes. Overall, a better understanding of how sex differences influence aging physiology is crucial to the prevention and treatment of neurodegenerative diseases.

Large artery stiffness and brain health: insights from animal models.

There are no effective treatments available to halt or reverse the progression of age-related cognitive decline and Alzheimer's disease. Thus, there is an urgent need to understand the underlying mechanisms of disease etiology and progression to identify novel therapeutic targets. Age-related changes to the vasculature, particularly increases in stiffness of the large elastic arteries, are now recognized as important contributors to brain aging. There is a growing body of evidence for an association between greater large artery stiffness and cognitive impairment among both healthy older adults and patients with Alzheimer's disease. However, studies in humans are limited to only correlative evidence, whereas animal models allow researchers to explore the causative mechanisms linking arterial stiffness to neurocognitive dysfunction and disease. Recently, several rodent models of direct modulation of large artery stiffness and the consequent effects on the brain have been reported. Common outcomes among these models have emerged, including evidence that greater large artery stiffness causes cerebrovascular dysfunction associated with increased oxidative stress and inflammatory signaling. The purpose of this mini-review is to highlight the recent findings associating large artery stiffness with deleterious brain outcomes, with a specific focus on causative evidence obtained from animal models. We will also discuss the gaps in knowledge that remain in our understanding of how large artery stiffness affects brain function and disease outcomes.

Transforming Psychiatry from the Classroom to the Clinic: Lessons from the National Neuroscience Curriculum Initiative.

OBJECTIVE: Individual residency programs often struggle to keep pace with scientific advances and new training requirements. Integrating a modern neuroscience perspective into the clinical practice of psychiatry is particularly emblematic of these challenges. The National Neuroscience Curriculum Initiative (NNCI) was established in 2013 to develop a comprehensive set of shared, open-access resources for teaching neuroscience in psychiatry. METHODS: The NNCI developed a collaborative, team-based approach with a peer-review process for generating and reviewing content. Teaching resources have included interactive sessions for the classroom paired with a comprehensive facilitator's guide. Brief accessible reviews and short videos have been developed for self-study and teaching in clinical settings. Dissemination efforts have included hands-on training for educators through national workshops. All resources are freely available on the NNCI website. Outcome measures have included the number of educational resources developed, feedback from workshop attendees, the number of US psychiatry residency programs who have adopted NNCI resources, as well as analytics from the NNCI website. RESULTS: To date, the NNCI has developed over 150 teaching sessions, reflecting the work of 129 authors from 49 institutions. The NNCI has run over 50 faculty development workshops in collaboration with numerous national and international organizations. Between March 2015 and June 2019, the website (www.NNCIonline.org) has hosted 48,640 unique users from 161 countries with 500,953 page views. More than 200 psychiatry training programs have reported implementing NNCI teaching materials. CONCLUSIONS: This multisite collaborative provides a model for integrating cutting-edge science into medical education and the practice of medicine more broadly.

The pro-atherogenic response to disturbed blood flow is increased by a western diet, but not by old age.

Atherogenic remodeling often occurs at arterial locations with disturbed blood flow (i.e., low or oscillatory) and both aging and western diet (WD) increase the likelihood for pro-atherogenic remodeling. However, it is unknown if old age and/or a WD modify the pro-atherogenic response to disturbed blood flow. We induced disturbed blood flow by partial carotid ligation (PCL) of the left carotid artery in young and old, normal chow (NC) or WD fed male B6D2F1 mice. Three weeks post-PCL, ligated carotid arteries had greater intima media thickness, neointima formation, and macrophage content compared with un-ligated arteries. WD led to greater remodeling and macrophage content in the ligated artery compared with NC mice, but these outcomes were similar between young and old mice. In contrast, nitrotyrosine content, a marker of oxidative stress, did not differ between WD and NC fed mice, but was greater in old compared with young mice in both ligated and un-ligated carotid arteries. In primary vascular smooth muscle cells, aging reduced proliferation, whereas conditioned media from fatty acid treated endothelial cells increased proliferation. Taken together, these findings suggest that the remodeling and pro-inflammatory response to disturbed blood flow is increased by WD, but is not increased by aging.

Deletion of Robo4 prevents high-fat diet-induced adipose artery and systemic metabolic dysfunction.

OBJECTIVE: Accumulating evidence suggests the vascular endothelium plays a fundamental role in the pathophysiology of obesity by regulating the functional status of white adipose and systemic metabolism. Robo4 is expressed specifically in endothelial cells and increases vascular stability and inhibits angiogenesis. We sought to determine the role of Robo4 in modulating cardiometabolic function in response to high-fat feeding. METHODS: We examined exercise capacity, glucose tolerance, and white adipose tissue artery gene expression, endothelium-dependent dilation (EDD), and angiogenesis in wild type and Robo4 knockout (KO) mice fed normal chow (NC) or a high-fat diet (HFD). RESULTS: We found Robo4 deletion enhances exercise capacity in NC-fed mice and HFD markedly increased the expression of the Robo4 ligand, Slit2, in white adipose tissue. Deletion of Robo4 increased angiogenesis in white adipose tissue and protected against HFD-induced impairments in white adipose artery vasodilation and glucose intolerance. CONCLUSIONS: We demonstrate a novel functional role for Robo4 in endothelial cell function and metabolic homeostasis in white adipose tissue, with Robo4 deletion protecting against endothelial and metabolic dysfunction associated with a HFD. Our findings suggest that Robo4-dependent signaling pathways may be a novel target in anti-obesity therapy.

Cerebral and skeletal muscle feed artery vasoconstrictor responses in a mouse model with greater large elastic artery stiffness.

NEW FINDINGS: What is the central question of this study? Greater large artery stiffness is associated with dysfunctional resistance artery vasodilatory responses, impaired memory and greater risk of Alzheimer's disease. However, it is unknown whether stiffer large arteries affect cerebral and skeletal muscle feed artery responses to vasoconstrictors. What is the main finding and its importance? In a mouse model with greater large artery stiffness (Eln+/- ), we find an exacerbated vasoconstrictor response to angiotensin II in cerebral arteries, but not skeletal muscle feed arteries, thus implicating altered cerebral artery angiotensin II responsiveness in the poor brain outcomes associated with greater large artery stiffness. ABSTRACT: Greater stiffness of the large elastic arteries is associated with end-organ damage and dysfunction. At the same time, resistance artery vasoconstrictor responsiveness influences vascular tone and organ blood flow. However, it is unknown whether large elastic artery stiffness modulates the responsiveness to vasoconstrictors in resistance arteries of the cerebral or skeletal muscle circulations. We previously described the elastin haploinsufficient (Eln+/- ) mouse as a model with greater aortic stiffness, but with similar cerebral and skeletal muscle feed artery stiffness to wild-type (Eln+/+ ) mice. Here, we used this model to examine the relationship between large elastic artery stiffness and resistance artery vasoconstrictor responses. In middle cerebral arteries (MCAs), vasoconstriction in response to angiotensin II (Ang II) was ∼40% greater in Eln+/- compared with Eln+/+ mice (P = 0.02), and this group difference was ameliorated by losartan, indicating a role for Ang II type 1 receptors (AT1Rs). In gastrocnemius feed arteries, Eln+/- and Eln+/+ mice did not differ in the response to Ang II. In addition, the vasoconstrictor responses to noradrenaline, endothelin-1 and potassium chloride were not different between Eln+/- and Eln+/+ mice for either MCAs or gastrocnemius feed arteries. The MCA AT1R gene expression did not differ between groups, whereas Ang II type 2 receptor gene expression was ∼50% lower in MCAs from Eln+/- versus Eln+/+ mice (P = 0.01). In conclusion, greater large elastic artery stiffness is associated with an exacerbated vasoconstriction response to Ang II in cerebral arteries, but is not associated with the responses to other vasoconstrictors in either cerebral or skeletal muscle feed arteries.

Induced Trf2 deletion leads to aging vascular phenotype in mice associated with arterial telomere uncapping, senescence signaling, and oxidative stress.

Age-related vascular dysfunction in large elastic and resistance arteries is associated with reductions in microvascular perfusion and elevations in blood pressure. Recent evidence indicates that telomere uncapping-induced senescence in vascular cells may be an important source of oxidative stress and vascular dysfunction in aging, but the causal relationship between these processes has yet to be elucidated. To test this important unexplored hypothesis, we measured arterial senescence signaling and oxidative stress, carotid and mesenteric artery endothelium-dependent vasodilatory capacity, markers of mesenteric microvascular perfusion and endothelial glycocalyx deterioration, and blood pressure in a novel mouse model of Cre-inducible whole body Trf2 deletion and telomere uncapping. Trf2 deletion led to a 320% increase in arterial senescence signaling (P < .05). There was a concurrent 29% and 22% reduction in peak endothelium-dependent vasodilation in carotid and mesenteric arteries, respectively, as well as a 63% reduction in mesenteric microvascular endothelial glycocalyx thickness (all P ≤ .01). Mesenteric microvascular perfusion was reduced by 8% and systolic blood pressure was increased by 9% following Trf2 deletion (both P < .05). Trf2 deletion also led to a pro-oxidative arterial phenotype characterized by increased in NADPH oxidase gene expression; a 210% increase in superoxide levels that was partly dependent on NADPH oxidase activity; and an oxidative stress mediated reduction in carotid artery vasodilation (all P ≤ .05). Collectively, our findings demonstrate that induced Trf2 deletion leads to telomere uncapping, increased senescence signaling, and oxidative stress mediated functional impairments in the vasculature similar to those seen in human aging.

Telomere uncapping and vascular aging.

Although most telomere biology research continues to focus on telomere shortening, there is increasing evidence that telomere deprotection, or "uncapping," is more biologically and possibly clinically important. Telomeres form t-loops to prevent the chromosome ends from appearing as a double-stranded DNA break and initiating a DNA damage response. Breakdown of the t-loop structure, referred to as uncapping, can lead to cellular senescence, increased oxidative stress, and inflammation in tissues. In this review, we describe how telomere uncapping potentially leads to age-related vascular dysfunction and increased cellular senescence, oxidative stress, and inflammation. Importantly, we present evidence to argue that telomere uncapping is more biologically relevant than telomere shortening and a better marker of vascular aging and target for antiaging interventions.