There is a very complex interaction between the brain and the cerebral vasculature to meet the metabolic demands of the brain for proper function. Preservation of vascular networks and ...cerebrovascular function ultimately plays a key role in this intricate communication within the brain in health and disease. Experimental evidence showed that diabetes not only affects the architecture of cerebral blood arteries causing adverse remodeling, pathological neovascularization, and vasoregression, but also alters cerebrovascular function resulting in compromised myogenic reactivity and endothelial dysfunction. Coupled with the disruption of blood brain barrier (BBB) integrity, changes in blood flow and microbleeds into the brain can rapidly occur. When an ischemic insult is superimposed on this pathology, not only is the neurovascular injury greater, but repair mechanisms fail, resulting in greater physical and cognitive deficits. While clinically it is known that women suffer disproportionately from diabetes as well as ischemic stroke and post-stroke cognitive impairment, the cerebrovascular architecture, patho/physiology, as well as cerebrovascular contributions to stroke recovery in female and diabetic animal models are inadequately studied and highlighted in this review.
Purpose of Review
To highlight important new findings on the topic of autoimmune disease-associated hypertension.
Recent Findings
Autoimmune diseases including systemic lupus erythematosus and ...rheumatoid arthritis are associated with an increased risk for hypertension and cardiovascular disease. A complex interaction among genetic, environmental, hormonal, and metabolic factors contribute to autoimmune disease susceptibility while promoting chronic inflammation that can lead to alterations in blood pressure. Recent studies emphasize an important mechanistic role for autoantibodies in autoimmune disease-associated hypertension. Moving forward, understanding how sex hormones, neutrophils, and mitochondrial dysfunction contribute to hypertension in autoimmune disease will be important.
Summary
This review examines the prevalent hypertension in autoimmune disease with a focus on the impact of immune system dysfunction on vascular dysfunction and renal hemodynamics as primary mediators with oxidative stress as a main contributor.
Long‐term disability due to stroke is a major global health burden, and there is an urgent need for interventions targeting the post‐acute phase of stroke to improve motor and cognitive deficits. ...Hypertension is a major contributor to overall risk for stroke and is associated with worse functional outcomes and mortality. Previous studies from our laboratory suggest that the spontaneously hypertensive rat (SHR) model of experimental hypertension develops profound, progressive post‐stroke cognitive impairment. Enriched housing (EH) conditions have shown promise as a rehabilitation strategy to enhance brain plasticity and improve behavior in preclinical studies using relatively young, healthy, adult male animals. However, the impact of hypertension on stroke recovery outcomes in response to EH remains unknown. The goal of this study was to test EH conditions for stroke rehabilitation in an established preclinical model of hypertension. We hypothesized that EH would improve the sensorimotor and cognitive recovery response to stroke in male SHRs compared to standard housing (SH) conditions. SHRs (aged 17w) were subjected to either sham or 60‐min. middle cerebral artery occlusion (MCAO) surgery to induce stroke. Stroke severity was controlled for using the following inclusion criteria: adhesive removal time (ART) > 35 sec. and either a modified Bederson score <= 6 or weight loss > 10%). Animals were then randomized to EH or SH conditions. EH conditions consisted of a novel environment to promote exercise and social interaction and was implemented for 2 hrs/day, 5 days/week for 4w starting 1w after surgery. Blood pressure was monitored by tail‐cuff plethysmography at baseline, 1, 3, and 7w post‐surgery. Animals were followed for an additional 4w after rehabilitation intervention for behavioral outcome measures. Motor recovery was assessed using ART (Figure 1), and novel object recognition (NOR, Figure 2) and 2‐trial Y‐maze were used to determine cognitive recovery. Stroked animals had significantly increased adhesive removal times at 3d and 6w post‐MCAO compared to sham animals, but EH conditions did not significantly impact this sensorimotor deficit. Stroke+EH animals had a significant decrease from their pre‐stroke recognition indices 1w post‐stroke compared to Sham+EH animals, suggesting there may have been some acute deficits in non‐spatial working memory. There were no significant differences among groups in time spent in the novel arm of the 2‐trial y‐maze, suggesting that stroke did not alter spatial working memory. Overall, these findings suggest that there are significant sensorimotor deficits post‐stroke, and the mild improvement in ART over time in stroked hypertensive animals occurs independently of EH. Cognitive deficits were similar in stroke and sham animals, regardless of rehabilitation, except for 1w post‐stroke, which is likely before EH would have had a significant impact on non‐spatial working memory. However, this effect might be skewed by a significant increase in NOR exploration time in Sham+EH animals. Unlike in previous studies in our laboratory, 60‐min. MCAO did not appear to induce significant post‐stroke cognitive impairment in these hypertensive animals compared to sham procedure.
Significant innovations in the management of acute ischemic stroke have led to an increased incidence in the long-term complications of stroke. Therefore, there is an urgent need for improvements in ...and refinement of rehabilitation interventions that can lead to functional and neuropsychological recovery. The goal of this review is to summarize the current progress and challenges involved with preclinical stroke recovery research. Moving forward, stroke recovery research should be placing an increased emphasis on the incorporation of comorbid diseases and biological variables in preclinical models in order to overcome translational roadblocks to establishing successful clinical rehabilitation interventions.
Patients with autoimmune rheumatic diseases including rheumatoid arthritis and systemic lupus erythematosus have an increased prevalence of hypertension. There is now a large body of evidence showing ...that the immune system is a key mediator in both human primary hypertension and experimental models. Many of the proposed immunological mechanisms leading to primary hypertension are paralleled in autoimmune rheumatic disorders. Therefore, examining the link between autoimmunity and hypertension can be informative for understanding primary hypertension. This review examines the prevalent hypertension, the immune mediators that contribute to the prevalent hypertension and their impact on renal function and how the risk of hypertension is potentially influenced by common hormonal changes that are associated with autoimmune rheumatic diseases.
Linked Articles
This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc
Diabetes and cognitive dysfunction, ranging from mild cognitive impairment to dementia, often coexist in individuals over 65 years of age. Vascular contributions to cognitive impairment/dementia ...(VCID) are the second leading cause of dementias under the umbrella of Alzheimer's disease and related dementias (ADRD). Over half of dementia patients have VCID either as a single pathology or a mixed dementia with AD. While the prevalence of type 2 diabetes in individuals with dementia can be as high as 39% and diabetes increases the risk of cerebrovascular disease and stroke, VCID remains to be one of the less understood and less studied complications of diabetes. We have identified cerebrovascular dysfunction and compromised endothelial integrity leading to decreased cerebral blood flow and iron deposition into the brain, respectively, as targets for intervention for the prevention of VCID in diabetes. This review will focus on targeted therapies that improve endothelial function or remove iron without systemic effects, such as agents delivered intranasally, that may result in actionable and disease-modifying novel treatments in the high-risk diabetic population.
Systemic lupus erythematosus (SLE) is an autoimmune disease that disproportionately affects women of reproductive age and increases their risk for developing hypertension, vascular, and renal ...disease. Relaxin has potential beneficial therapeutic effects in cardiovascular disease through direct actions on the vasculature. The potential therapeutic benefit of relaxin on SLE-associated cardiovascular and renal risk factors like hypertension has not previously been tested. We hypothesized that relaxin would attenuate hypertension, renal injury, and vascular dysfunction in an established female mouse model of SLE (NZBWF1 mice). Serelaxin (human recombinant relaxin-2, 0.5 mg·kg
·day
) or vehicle was administered via osmotic mini-pump for 4 wk in female control (NZW) or SLE mice between 28 and 31 wk of age. Serelaxin treatment increased uterine weights in both groups, suggesting that the Serelaxin was bioactive. Mean arterial pressure, measured by carotid artery catheter, was significantly increased in vehicle-treated SLE mice compared with vehicle-treated controls, but was not changed by Serelaxin treatment. Albumin excretion rate, measured by ELISA, was similar between vehicle- and Serelaxin-treated SLE mice and between vehicle- and Serelaxin-treated control mice. Wire myography was performed using isolated carotid arteries to assess endothelial-independent and -dependent vasodilation, and data confirm that SLE mice have impaired endothelium-independent and -dependent relaxation compared with control mice. Serelaxin treatment did not affect endothelium-independent vasodilation, but exacerbated the endothelium-dependent dysfunction. These data suggest that, contrary to our hypothesis, Serelaxin infusion does not attenuate hypertension, renal injury, or vascular dysfunction in SLE, but worsens underlying vascular endothelial dysfunction in this experimental model of SLE. These data do not support the use of human recombinant relaxin-2 as an antihypertensive in the SLE patient population.
Relaxin is a peptide hormone commonly known for its role in pregnancy and for its use in recent clinical trials for the treatment of heart failure. Evidence suggests that relaxin has immunomodulatory effects; however, the potential therapeutic impact of relaxin in chronic immune mediated disease is unclear. This study tests whether recombinant human relaxin (Serelaxin) attenuates the progression of autoimmunity, and the associated cardiovascular consequences, in an experimental model of systemic lupus erythematosus.
Cardiovascular disease is the major cause of mortality among patients with the autoimmune disorder systemic lupus erythematosus (SLE). Our laboratory previously reported that immunosuppression with ...mycophenolate mofetil, a common therapy in patients with SLE, attenuates the development of hypertension in an experimental model of SLE. Cyclophosphamide (CYC) is another common therapy for patients with SLE that has contributed to improved disease management; however, its impact on the development of hypertension associated with SLE is not clear. We tested whether treatment with CYC (25 mg/kg, once/week, IP injection) for 4 weeks would attenuate hypertension in an established female mouse model of SLE with hypertension (30‐week‐old NZBWF1 females). Plasma anti‐dsDNA IgG levels, pathogenic for the disease, were lower in CYC‐treated SLE mice compared to vehicle‐treated SLE mice, suggesting efficacy of the therapy to suppress aberrant immune system function. Mean arterial pressure (MAP) was assessed by carotid artery catheters in conscious mice. Treatment did not attenuate the development of hypertension when compared to vehicle‐treated SLE mice; however, urinary albumin excretion was lower in CYC‐treated animals. Corresponding with the reduction in autoantibodies, data suggest that CYC treatment lowered circulating CD45R+ B cells. Paradoxically, circulating CD11b+Ly6G+ neutrophils were increased in CYC‐treated SLE mice compared to vehicle treated. Estrus cycling data also suggest that CYC treatment had an impact on ovarian function that may be consistent with reduced circulating estrogen levels. Taken together, these data suggest that CYC treatment attenuates autoantibody production and renal disease during SLE, but that the potential to affect MAP may be blunted by the increase in circulating neutrophils and CYC's impact on ovarian function.
The impact of immunosuppression with cyclophosphamide (CYC) on blood pressure during autoimmune disease was examined. Although CYC protected the kidneys and reduced the markers of immune system activation, treatment did not affect blood pressure. The treatment altered ovarian function suggesting the possibility that ovarian toxicity may have prevented potential antihypertensive actions of CYC.
A unified scheme to assign pollen samples to vegetation types was used to reconstruct vegetation patterns north of 55°N at the last glacial maximum (LGM) and mid‐Holocene (6000 years B.P.). The ...pollen data set assembled for this purpose represents a comprehensive compilation based on the work of many projects and research groups. Five tundra types (cushion forb tundra, graminoid and forb tundra, prostrate dwarf‐shrub tundra, erect dwarf‐shrub tundra, and low‐ and high‐shrub tundra) were distinguished and mapped on the basis of modern pollen surface samples. The tundra‐forest boundary and the distributions of boreal and temperate forest types today were realistically reconstructed. During the mid‐Holocene the tundra‐forest boundary was north of its present position in some regions, but the pattern of this shift was strongly asymmetrical around the pole, with the largest northward shift in central Siberia (∼200 km), little change in Beringia, and a southward shift in Keewatin and Labrador (∼200 km). Low‐ and high‐shrub tundra extended farther north than today. At the LGM, forests were absent from high latitudes. Graminoid and forb tundra abutted on temperate steppe in northwestern Eurasia while prostrate dwarf‐shrub, erect dwarf‐shrub, and graminoid and forb tundra formed a mosaic in Beringia. Graminoid and forb tundra is restricted today and does not form a large continuous biome, but the pollen data show that it was far more extensive at the LGM, while low‐ and high‐shrub tundra were greatly reduced, illustrating the potential for climate change to dramatically alter the relative areas occupied by different vegetation types.
Introduction
Post‐stroke cognitive impairment (PSCI) contributes to significant long‐term disability in stroke victims. 30% of ischemic stroke victims in the United States also have diabetes, which ...increases the risk of hemorrhagic transformation as well as PSCI. Ferroptosis, an iron‐induced cell death can instigate increased oxidative stress and contribute to impaired neurovascular repair leading to PSCI in diabetes. In our previous studies, we were able to identify that treating diabetic animals with an iron chelator, deferoxamine (DFX), prevents post‐stroke vasoregression and improves functional outcomes. Furthermore, DFX prevented the activation of ferroptosis in brain microvascular endothelial cells in vitro. Untreated diabetic animals experienced progressive cognitive decline while being monitored for 8 weeks. These findings led us to speculate that endothelial ferroptosis also plays a role in vasoregression and impacts cognitive outcomes post‐stroke. Therefore, this study was designed to test the hypothesis that inhibiting ferroptosis in the post‐stroke period will improve cognitive recovery in diabetic animals.
Methods
Animals were housed in reverse light cycle. 8 weeks after diabetes onset, male rats underwent 60 min middle cerebral artery occlusion (MCAO). On Day 3, after stroke injury was confirmed by MRI, animals were randomized to UAMC‐3 (2mg/kg) or vehicle treatment for 2 weeks. Sensorimotor and cognitive behavioral tests were performed during the animals’ active hours up to 8 weeks post MCAO.
Results
(Table 1): 60 min occlusion caused significant acute neurological deficits. There were no differences between the groups in indices measured by novel object recognition (NOR), Y‐maze and sucrose preference tests. Interestingly, step through latency in passive avoidance test (PAT) was lower in the UAMC‐3203 group.
Conclusion
Treatment with a ferroptosis inhibitor for 2 weeks after stroke did not impact recognition and working memory but worsened aversive learning in diabetic male rats. Unlike our previous study in which behavior tests were performed during rats’ passive hours, there was no progressive cognitive decline in untreated animals. Further evaluation of behavior testing times as well as tissue markers of neurovascular degeneration, inflammation and ferroptosis are required to determine whether molecular and cellular markers are affected by the treatment before overt changes in behavioral outcomes.
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