Acute Vascular Injury Research Articles

Vascular Stress Markers Following Inhalation of Heated Tobacco Products: A Study on Extracellular Vesicles.

The advent of heated tobacco products (HTPs) has introduced new variables in the study of nicotine delivery systems and their health implications. Amidst concerns over cardiovascular effects, this study aims to elucidate the acute impact of HTP inhalation on extracellular vesicles (EV) levels in young, healthy individuals. In this controlled, acute exposure study, 23 young, healthy volunteers were subjected to HTP inhalation. EV levels of endothelial and platelet origin were quantified through flow cytometry before and after exposure. Data analysis was performed using multiple measures ANOVA to assess changes in EV concentrations. Our findings reveal a significant increase in EVs of endothelial and platelet origin following short-term HTP inhalation with nicotine. Notably, no significant change was observed in leukocyte- and neutrophil-derived EVs. This increase in EVs suggests acute vascular stress, with peak levels observed 4h post-exposure. The rise in endothelial and platelet-derived EVs aligns with documented responses to acute vascular injury, paralleling the effects seen with traditional cigarette and e-cigarette use. Despite HTPs being marketed as safer alternatives, our results indicate that nicotine-containing HTPs may still pose significant vascular risks. These findings contribute to the growing body of evidence cautioning against the perceived safety of HTPs and reinforce the importance of regulatory oversight and public health initiatives targeting nicotine delivery technologies. Trial Registrations: ClinicalTrials.gov ID: NCT04824495, registered 2021-01-07.

Fever Prevention in Patients With Acute Vascular Brain Injury: The INTREPID Randomized Clinical Trial.

Fever is associated with worse outcomes in patients with stroke, but whether preventing fever improves outcomes is unclear. To determine whether fever prevention after acute vascular brain injury is achievable and impacts functional outcome. Open-label randomized clinical trial with blinded outcome assessment that enrolled 686 of 1176 planned critically ill patients with stroke at 43 intensive care units in 7 countries from March 2017 to April 2021 (last date of follow-up was May 12, 2022). Patients randomized to fever prevention (n = 339) were targeted to 37.0 °C for 14 days or intensive care unit discharge using an automated surface temperature management device. Standard care patients (n = 338) received standardized tiered fever treatment on occurrence of temperature of 38 °C or greater. Primary outcome was daily mean fever burden: the area under the temperature curve above 37.9 °C (total fever burden) divided by the total number of hours in the acute phase, multiplied by 24 hours (°C-hour). The principal secondary outcome was 3-month functional recovery by shift analysis of the 6-category modified Rankin Scale, which is scored from 0 (no symptoms) to 6 (death). Major adverse events included death, pneumonia, sepsis, and malignant cerebral edema. Enrollment was stopped after a planned interim analysis demonstrated futility of the principal secondary end point. In total, 686 patients were enrolled, and 9 were consented but not randomized, leaving a primary analysis population of 677 patients (254 ischemic stroke, 223 intracerebral hemorrhage, 200 subarachnoid hemorrhage; 345 were female [51%]; median age, 62 years) with 433 (64%) completing the study through 12 months. Daily mean (SD) fever burden was significantly lower in the fever prevention group (0.37 [1.0] °C-hour; range, 0.0-8.0 °C-hour) compared with the standard care group (0.73 [1.1] °C-hour; range, 0.0-10.3 °C-hour) (difference, -0.35 [95% CI, -0.51 to -0.20]; P < .001). Between-group differences for the primary outcome by stroke subtype were -0.10 (95% CI, -0.35 to 0.15) for ischemic stroke, -0.50 (95% CI, -0.78 to -0.22) for intracerebral hemorrhage, and -0.52 (95% CI, -0.81 to -0.23) for subarachnoid hemorrhage (all P < .001 by Wilcoxon rank-sum test). There was no significant difference in functional recovery at 3 months (median modified Rankin Scale score, 4.0 vs 4.0, respectively; odds ratio for a favorable shift in functional outcome, 1.09 [95% CI, 0.81 to 1.46]; P = .54). Major adverse events occurred in 82.2% of participants in the fever prevention group vs 75.9% in the standard care group, including 33.8% vs 34.5% for infections, 14.5% vs 14.0% for cardiac disorders, and 24.5% vs 20.5% for respiratory disorders. In patients with acute vascular brain injury, preventive normothermia using an automated surface temperature management device effectively reduced fever burden but did not improve functional outcomes. ClinicalTrials.gov Identifier: NCT02996266.

Dynamic changes in proresolving lipid mediators and their receptors following acute vascular injury in male rats.

Acute vascular injury provokes an inflammatory response, resulting in neointimal hyperplasia (NIH) and downstream pathologies. The resolution of inflammation is an active process in which specialized proresolving lipid mediators (SPM) and their receptors play a central role. We sought to examine the acute phase response of SPM and their receptors in both circulating blood and the arterial wall in a rat angioplasty model. We found that the ratio of proresolving to pro-inflammatory lipid mediators (LM) in plasma decreased sharply 1 day after vascular injury, then increased slightly by day 7, while that in arteries remained depressed. Granulocyte expression of SPM receptors ALX/FPR2 and DRV2/GPR18, and a leukotriene B4 receptor BLT1 increased postinjury, while ERV1/ChemR23 expression was reduced early and then recovered by day 7. Importantly, we show unique arterial expression patterns of SPM receptors in the acute setting, with generally low levels through day 7 that contrasted sharply with that of the pro-inflammatory CCR2 receptor. Overall, these data document acute, time-dependent changes of LM biosynthesis and SPM receptor expression in plasma, leukocytes, and artery walls following acute vascular injury. A biochemical imbalance between inflammation and resolution LM pathways appears persistent 7 days after angioplasty in this model. These findings may help guide therapeutic approaches to accelerate vascular healing and improve the outcomes of vascular interventions for patients with advanced atherosclerosis.

Smooth muscle-derived adventitial progenitor cells direct atherosclerotic plaque composition complexity in a Klf4-dependent manner.

We previously established that vascular smooth muscle-derived adventitial progenitor cells (AdvSca1-SM) preferentially differentiate into myofibroblasts and contribute to fibrosis in response to acute vascular injury. However, the role of these progenitor cells in chronic atherosclerosis has not been defined. Using an AdvSca1-SM cell lineage tracing model, scRNA-Seq, flow cytometry, and histological approaches, we confirmed that AdvSca1-SM-derived cells localized throughout the vessel wall and atherosclerotic plaques, where they primarily differentiated into fibroblasts, smooth muscle cells (SMC), or remained in a stem-like state. Krüppel-like factor 4 (Klf4) knockout specifically in AdvSca1-SM cells induced transition to a more collagen-enriched fibroblast phenotype compared with WT mice. Additionally, Klf4 deletion drastically modified the phenotypes of non-AdvSca1-SM-derived cells, resulting in more contractile SMC and atheroprotective macrophages. Functionally, overall plaque burden was not altered with Klf4 deletion, but multiple indices of plaque composition complexity, including necrotic core area, macrophage accumulation, and fibrous cap thickness, were reduced. Collectively, these data support that modulation of AdvSca1-SM cells through KLF4 depletion confers increased protection from the development of potentially unstable atherosclerotic plaques.

Smooth muscle cells-specific loss of OCT4 accelerates neointima formation after acute vascular injury.

There is growing evidence that smooth muscle cell (SMC) phenotypic transitions play critical roles during normal developmental and tissue recovery processes and in pathological conditions such as atherosclerosis. However, the molecular mechanisms responsible for these transitions are not well understood. Recently, we found that the embryonic stem cell/induced pluripotent stem cell (iPSC) factor OCT4, which was believed to be silenced in somatic cells, plays an atheroprotective role in SMC, and regulates angiogenesis after corneal alkali burn and hindlimb ischemia by mediating microvascular SMC and pericyte migration. However, the kinetics of OCT4 activation in arterial SMC and its role in acute pathological conditions are still unknown. Here, using an Oct4-IRES-GFP reporter mouse model, we found that OCT4 is reactivated in the carotid artery 18 hours post-acute ligation-induced injury, a common in vivo model of the SMC phenotypic transitions. Next, using a tamoxifen-inducible Myh11-CreERT2 Oct4 knockout mouse model, we found that the loss of OCT4, specifically in SMC, led to accelerated neointima formation and increased tunica media following carotid artery ligation, at least in part by increasing SMC proliferation within the media. Bulk RNA sequencing analysis on the cultured SMC revealed significant down-regulation of the SMC contractile markers and dysregulation of the genes belonging to the regulation of cell proliferation and, positive and negative regulation for cell migration ontological groups following genetic inactivation of Oct4. We also found that loss of Oct4 resulted in suppression of contractile SMC markers after the injury and in cultured aortic SMC. Further mechanistic studies revealed that OCT4 regulates SMC contractile genes, ACTA2 and TAGLN, at least in part by direct binding to the promoters of these genes. These results demonstrate that the pluripotency factor OCT4 is quickly activated in SMC after the acute vascular injury and inhibits SMC hyperproliferation, which may be protective in preventing excessive neointima formation.

Prognostic Neuroimaging Biomarkers in Acute Vascular Brain Injury and Traumatic Brain Injury.

Prognostic imaging biomarkers after acute brain injury inform treatment decisions, track the progression of intracranial injury, and can be used in shared decision-making processes with families. Herein, key established biomarkers and prognostic scoring systems are surveyed in the literature, and their applications in clinical practice and clinical trials are discussed. Biomarkers in acute ischemic stroke include computed tomography (CT) hypodensity scoring, diffusion-weighted lesion volume, and core infarct size on perfusion imaging. Intracerebral hemorrhage biomarkers include hemorrhage volume, expansion, and location. Aneurysmal subarachnoid biomarkers include hemorrhage grading, presence of diffusion-restricting lesions, and acute hydrocephalus. Traumatic brain injury CT scoring systems, contusion expansion, and diffuse axonal injury grading are reviewed. Emerging biomarkers including white matter disease scoring, diffusion tensor imaging, and the automated calculation of scoring systems and volumetrics are discussed.

Incidence of Acute Vascular Injury Associated with Fracture Distal Radius

Incidence of Acute Vascular Injury Associated with Fracture Distal Radius

Dyslipidemia among Patients with Ischemic Stroke Admitted to the Department of Medicine of a Tertiary Care Centre.

Sudden neurological deficits due to an acute focal vascular injury of the central nervous system is stroke. It is a major cause of morbidity and mortality. Dyslipidemia is any abnormality in the parameter of the lipid profile which has been associated with stroke. The aim of this study was to find out the prevalence of dyslipidemia among patients with ischemic stroke in the Department of Medicine of a tertiary care centre. A descriptive cross-sectional study was conducted in a tertiary care centre among admitted ischemic stroke patients from 5 August 2022 to 14 March 2023 after obtaining ethical approval from the Institutional Review Committee. Overnight fasting blood samples were collected for lipid profile. Convenience sampling method was used. The point estimate was calculated at a 95% Confidence Interval. Among 79 ischemic stroke patients, 42 (53.16%) (42.09-64.23, at 95% Confidence Interval) had dyslipidemia where high cholesterol was seen in 21 (50%), high triglyceride in 22 (52.38%), high low-density lipoprotein 14 (33.33%) and low high-density lipoprotein in 20 (47.61%). The prevalence of dyslipidemia among ischemic stroke patients was lower than the similar studies done in similar settings. cross-sectional studies; dyslipidemia; hyperlipidemias; ischemic stroke.

Relationship between Family Support and Compliance of Post-Stroke Clients Undergoing Physiotherapy in the Medical Rehabilitation Room of Pariaman Hospital

One of the degenerative diseases whose incidence has increased recently is stroke. The recovery rate of stroke is still low, as many as 15-30% of patients will experience paralysis. One of the healing processes is to follow the physiotherapy program. In the physiotherapy unit of Pariaman Hospital, more than half (50%) were not compliant with physiotherapy. The purpose of this study was to determine the relationship between family support and client compliance with physiotherapy in the physiotherapy unit of Pariaman Hospital.Stroke is an acute vascular injury to the brain, or a severe and sudden injury to the blood vessels of the brain. Injury can be caused by blockage of blood clots, narrowing of blood vessels, blockage or rupture of blood vessels. Physiotherapy is a health service that is carried out for the healing process. The implementation is in accordance with the degree of disability experienced by the client. This research is descriptive analytic with cross sectional approach. The population is stroke clients who follow physiotherapy in the physiotherapy unit of Pariaman Hospital, with sampling techniques using accidental sampling which amounted to 52 people. Data were collected by interview in accordance with the questionnaire provided and the data were processed by SPSS and then analyzed univariately and bivariately. The results of this study obtained 28 (53.8%) family support that played a role there were 3 (10.7%) clients who were not compliant with undergoing physiotherapy and from 24 (46.2%) family support did not play a role there were 22 (91.7%) clients who were not compliant with undergoing physiotherapy, P Value = 0.025 &lt;0.05 means Ha accepts which means there is a significant relationship between family support and compliance with undergoing physiotherapy for post-stroke patients in the medical rehabilitation room of Pariaman Hospital. to increase client compliance, health workers can provide counseling on the importance of family support in increasing stroke client compliance to follow physiotherapy for the client's healing process.

Abstract P3023: Endothelial Pparδ Deletion Exacerbates Endotoxemia-Induced Vascular Injury And Inflammation

Rationale and Background: Impairment of vascular endothelial integrity is one of the hallmarks of acute lung injury, which underlies leukocyte infiltration and edema formation and contributes to organ dysfunction. The peroxisome proliferator-activated receptor delta (PPARδ) is a transcription factor regulating vascular endothelial cell (EC) function. Our previous study revealed that selective deletion of PPARδ in the endothelium worsens ischemic vascular injury, disrupts endothelial integrity, and exacerbates vascular inflammation in a mouse model of hindlimb ischemia. Methods and Results: In this study, we investigated whether PPARδ is protective for EC function in acute vascular injury and inflammation in the mouse lung. We performed lipopolysaccharide (LPS)-induced endotoxemia in the EC-selective PPARδ knockout mice (Ppard EC-KO ) and their wild-type littermates (Ppard EC-WT ). The mortality of Ppard EC-KO mice was higher after LPS injection. The survived Ppard EC-KO mice showed more severe lung vascular inflammation suggested by sustained leukocyte infiltration in the lung tissues and in the bronchoalveolar fluid, more pro-inflammatory cytokine production, and higher expression of EC activation markers CCL2, ICAM1, VCAM1, and E-selectin. In addition, the lung endothelium of LPS-treated Ppard EC-KO mice has degraded endothelial glycocalyx and discontinuous EC junctions, resulting in increased vascular leakage. In vitro experiments using human lung microvascular endothelial cells (HLMVECs) revealed that silencing PPARδ downregulated the expressions of ZO-1, claudin-5, and VE-cadherin, and altered their membrane distribution, leading to hyperpermeability of EC monolayer, at basal level and also in the presence of LPS or TNFα. Silencing of PPARδ also induces more activation of pro-inflammatory transcription factors including STAT1, IRF3, and IRF7. Conclusion: In summary, our study showed the protective role of endothelial PPARδ against endotoxemia-induced disruption of vascular barrier function and vascular inflammation in the lung endothelium. (Supported by Hong Kong Research Grant Council GRF 14107822 and 14105321)

Redistribution of the chromatin remodeler Brg1 directs smooth muscle-derived adventitial progenitor-to-myofibroblast differentiation and vascular fibrosis.

Vascular smooth muscle-derived Sca1+ adventitial progenitor (AdvSca1-SM) cells are tissue-resident, multipotent stem cells that contribute to progression of vascular remodeling and fibrosis. Upon acute vascular injury, AdvSca1-SM cells differentiate into myofibroblasts and are embedded in perivascular collagen and the extracellular matrix. While the phenotypic properties of AdvSca1-SM-derived myofibroblasts have been defined, the underlying epigenetic regulators driving the AdvSca1-SM-to-myofibroblast transition are unclear. We show that the chromatin remodeler Smarca4/Brg1 facilitates AdvSca1-SM myofibroblast differentiation. Brg1 mRNA and protein were upregulated in AdvSca1-SM cells after acute vascular injury, and pharmacological inhibition of Brg1 by the small molecule PFI-3 attenuated perivascular fibrosis and adventitial expansion. TGF-β1 stimulation of AdvSca1-SM cells in vitro reduced expression of stemness genes while inducing expression of myofibroblast genes that was associated with enhanced contractility; PFI blocked TGF-β1-induced phenotypic transition. Similarly, genetic knockdown of Brg1 in vivo reduced adventitial remodeling and fibrosis and reversed AdvSca1-SM-to-myofibroblast transition in vitro. Mechanistically, TGF-β1 promoted redistribution of Brg1 from distal intergenic sites of stemness genes and recruitment to promoter regions of myofibroblast-related genes, which was blocked by PFI-3. These data provide insight into epigenetic regulation of resident vascular progenitor cell differentiation and support that manipulating the AdvSca1-SM phenotype will provide antifibrotic clinical benefits.

Abstract 398: Impaired Macrophage Interleukin-1β-Dependent Wound Healing In The Context Of Diabetes

Peripheral Artery Disease (PAD), associated with diabetes, is an atherosclerotic vascular disease with impaired angiogenesis and poor wound healing. Increasing data support early inflammation as playing a key role in setting the state for adequate recovery following acute vascular injury. Here, we sought to understand the impact of diabetes upon IL-1β-dependent angiogenesis during wound healing. We identified an important role for inflammatory macrophage IL-1β-driven vascular endothelial growth factor-A (VEGF-A) production during angiogenesis required for wound healing. To determine the role of IL-1β signaling in the context of diabetes, we used a macrophage-specific IL-1 β -deletion model ( mIL-1 β ), a macrophage-specific IL-1R -deletion model ( mIL-1R ), and a Leptin ( Lepr db/db ) model. Using a punch biopsy model, wound closure was quantified over ten days. Mice with diabetes ( Lepr db/db ) demonstrate initial wound expansion, followed by delayed wound closure. Comparable results were found using mIL-1 β mice, suggesting that mice with diabetes may phenocopy disrupted IL-1β signaling. Analysis from all three models confirmed decreased macrophage expression of pro-angiogenic VEGF-A in response to IL-1β signaling in vitro and reduced VEGF-A expression in wounds in vivo . We examined the impact of upregulating IL-1β-dependent transcription factors, STAT3 and NF-κB, to bypass the impairment conferred by diabetes and found that constitutively active STAT3 and IKK-2 (NF-κB activator) appear to reconstitute VEGF-A expression in macrophages. In summary, angiogenesis dependent healing requires the contribution of macrophage IL-1β-dependent VEGF-A expression in the early inflammatory state, and diabetes is associated with an impairment in this pathway. Therapeutic angiogenesis strategies in the context of diabetes may require upregulation of transcription factors downstream of IL-1β to restore macrophage VEGF-A expression that is required for angiogenesis-dependent wound healing.

Abstract 363: Resident Vascular Adventitial Progenitor Cells Of Smooth Muscle Cell-lineage Adopt Profibrotic Phenotype And Contribute To Cardiac Fibrosis.

Cardiac myofibroblasts are the major contributors to ECM deposition in pathological cardiovascular fibrosis, which is the characteristic feature of cardiovascular diseases. However, due to potential heterogeneity of myofibroblasts, the origin of these cells remains controversial. Using highly specific smooth muscle cell lineage-tracing mouse models, we discovered the smooth muscle cell origin of a subpopulation of resident vascular adventitial progenitor cells, defined by the expression of the stem cell marker Sca1 (AdvSca1-SM cells), which rapidly proliferate and adopt a myofibroblast phenotype in response to acute vascular injury. Further, we identified a specific gene signature of active hedgehog/Wnt/β-catenin/Klf4 signaling in AdvSca1-SM cells and validated a Gli1-CreERT2-ROSA26-YFP (Gli1) reporter mouse model to be a faithful lineage tracing system for AdvSca1-SM cells. However, the function of AdvSca1-SM cells in cardiac fibrosis is unknown. Using immunofluorescent staining and label-free second harmonic generation (SHG) imaging, we observed the expansion and migration of AdvSca1-SM cells in close association with perivascular and interstitial cardiac fibrosis in pressure overload-induced cardiac fibrosis in Gli1 reporter mice. By integrating single cell RNA sequencing (scRNA-seq) with spatial transcriptomics, we identified a AngII-driven spatiotemporal profibrotic differentiation trajectory of AdvSca1-SM cells in mouse cardiac tissue. The trajectory, characterized by loss of expression of stemness genes, such as Klf4 , the lncRNA, Meg3 , and up-regulation of myofibroblast genes, was recapitulated in human RNA-seq data and of translational significance. Connectivity map analysis of the scRNA-seq data identified statins as potential candidates for inhibition of the profibrotic transition of AdvSca1-SM cells. In agreement, simvastatin induced the expression of stemness genes and inhibited TGFβ-induced up-regulation of αSMA and down-regulation of KLF4 in cultured AdvSca1-SM cells. Lentiviral-mediated up-regulation of Meg3 also rescued TGFβ-induced suppression of stemness genes. Our findings support the further development of anti-fibrotic therapeutics targeting AdcSca1-SM cells.

Intensive receptor blockade and plasma exchange to treat refractory scleroderma renal crisis in patients with agonistic autoantibodies targeting the angiotensin II type 1 and endothelin-1 type A receptors

Scleroderma renal crisis is a rare complication of systemic sclerosis characterized by a rapid decline in kidney function due to acute renal vascular injury. Recently, activating autoantibodies targeting the angiotensin II type 1 receptor and the endothelin-1 type A receptor have been implicated in the pathophysiology of scleroderma renal crisis by sensitizing the angiotensin II type 1 receptor and endothelin-1 type A receptor in renal resistance arteries to their natural ligands. Here, we describe a cohort of 10 patients with scleroderma renal crisis refractory to standard treatment, including blockade of the renin-angiotensin system. Multimodal therapy was initiated, targeting at the removal of anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies by plasma exchange and the reduction of vasoconstrictive activity. Further treatment options included angiotensin II type 1 receptor and endothelin-1 type A receptor blockade, iloprost, intravenous immunoglobulins, and immunosuppression. Six patients were hypertensive. On kidney biopsy, concentric intimal sclerosis was present in all patients, whereas acute vascular injury was evident in eight. Levels of anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies were significantly reduced by multimodal treatment. Kidney function improved in three patients with histological signs of severe acute renal vascular damage. This report demonstrates that intensive multimodal therapy taking account of potentially pathogenic anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies in concert with other vasodilatory interventions provides a salvage option for patients with refractory scleroderma renal crisis.

Mechanisms of gas transfer impairment utilizing nitric oxide following severe COVID-19 pneumonitis.

Reduced carbon monoxide diffusing capacity (DLCO ) is common after recovery from severe COVID-19 pneumonitis. The extent to which this relates to alveolar membrane dysfunction as opposed to vascular injury is uncertain. Simultaneous measurement of nitric oxide diffusing capacity (DLNO ) and DLCO can partition gas diffusion into its two components: alveolar-capillary membrane conductance (DmCO ) and capillary blood volume (VC ). We sought to evaluate DmCO and VC in the early and later recovery periods after severe COVID-19. Patients attended for post-COVID-19 clinical review and lung function testing including DLNO /DLCO . Repeat testing occurred when indicated and comparisons made using t-tests. Forty-nine (eight female) subjects (mean ± SD age: 58 ± 13, BMI: 34 ± 8) who had severe COVID-19 pneumonitis, WHO severity classification of 6 ± 1, and prolonged (21 ± 22 days) hospital stay, were assessed 2 months (61 ± 35 days) post discharge. DLCO adj (z-score -1.70 ± 1.49, 25/49 < lower limit of normal [LLN]) and total lung capacity (z-score -1.71 ± 1.30) were both reduced. DmCO and VC and were reduced to a similar extent (z-score -1.19 ± 1.05 and -1.41 ± 1.20, p = 0.4). Seventeen (one female) patients returned for repeat testing 4 months (122 ± 61 days) post discharge. In this subgroup with more impaired lung function, DLCO adj improved but remained below LLN (z-score -3.15 ± 0.83 vs. -2.39 ± 0.86, p = 0.01), 5/17 improved to >LNN. DmCO improved (z-score -2.05 ± 0.89 vs. -1.41 ± 0.78, p = 0.01) but VC was unchanged (z-score -2.51 ± 0.55 vs. -2.29 ± 0.59, p = 0.16). Alveolar membrane conductance is abnormal in the earlier recovery phase following severe COVID-19 but significantly improves. In contrast, reduced VC persists. These data raise the possibility that persisting effects of acute vascular injury may contribute to gas diffusion impairment long after severe COVID-19 pneumonitis.

Evaluation of vascular repair by tissue-engineered human acellular vessels or expanded polytetrafluoroethylene grafts in a porcine model of limb ischemia and reperfusion.

This study evaluated performance of a tissue-engineered human acellular vessel (HAV) in a porcine model of acute vascular injury and ischemia. The HAV is an engineered blood vessel consisted of human vascular extracellular matrix proteins. Limb reperfusion and vascular outcomes of the HAV were compared with those from synthetic expanded polytetrafluoroethylene (ePTFE) grafts. Thirty-six pigs were randomly assigned to four treatment groups, receiving either the HAV or a PTFE graft following a hind limb ischemia period of either 0 or 6 hours. All grafts were 3-cm-long interposition 6-mm diameter grafts implanted within the right iliac artery. Animals were not immunosuppressed and followed for up to 28 days after surgery. Assessments performed preoperatively and postoperatively included evaluation of graft patency, hind limb function, and biochemical markers of tissue ischemia or reperfusion injury. Histological analysis was performed on explants to assess host cell responses. Postoperative gait assessment and biochemical analysis confirmed that ischemia and reperfusion injury were caused by 6-hour ischemia, regardless of vascular graft type. Hind limb function and tissue damage biomarkers improved in all groups postoperatively. Final patency rates at postoperative day 28 were higher for HAV than for ePTFE graft in both the 0-hour (HAV, 85.7%; ePTFE, 66.7%) and 6-hour (HAV, 100%; ePTFE, 75%) ischemia groups, but these differences were not statistically significant. Histological analyses identified some intimal hyperplasia and host reactivity to the xenogeneic HAV and also to the synthetic ePTFE graft. Positive host integration and vascular cell infiltration were identified in HAV but not ePTFE explants. Based on the functional performance and the histologic profile of explanted HAVs, this study supports further investigation to evaluate long-term performance of the HAV when used to repair traumatic vascular injuries.

Tissue factor targeting peptide enhances nanoparticle binding and delivery of a synthetic specialized pro-resolving lipid mediator to injured arteries

BackgroundSpecialized pro-resolving lipid mediators (SPM) such as resolvin D1 (RvD1) attenuate inflammation and exhibit vasculo-protective properties. MethodsWe investigated poly-lactic-co-glycolic acid (PLGA)-based nanoparticles (NP), containing a peptide targeted to tissue factor (TF) for delivery of 17R-RvD1 and a synthetic analog 17-R/S-benzo-RvD1 (benzo-RvD1) using in vitro and in vivo models of acute vascular injury. NPs were characterized in vitro by size, drug loading, drug release, TF binding, and vascular smooth muscle cell migration assays. NPs were also characterized in a rat model of carotid angioplasty. ResultsPLGA NPs based on a 75/25 lactic to glycolic acid ratio demonstrated optimal loading (507.3 pg 17R-RvD1/mg NP; P = ns) and release of RvD1 (153.1 pg 17R-RvD1/mg NP; P < .05). NPs incorporating the targeting peptide adhered to immobilized TF with greater avidity than NPs with scrambled peptide (50 nM: 41.6 ± 0.52 vs 32.66 ± 0.34; 100 nM: 35.67 ± 0.95 vs 23.5 ± 0.39; P < .05). NPs loaded with 17R-RvD1 resulted in a trend toward blunted vascular smooth muscle cell migration in a scratch assay. In a rat model of carotid angioplasty, 16-fold more NPs were present after treatment with TF-targeted NPs compared with scrambled NPs (P < .01), with a corresponding trend toward higher tissue levels of 17R-RvD1 (P = .06). Benzo-RvD1 was also detectable in arteries treated with targeted NP delivery and accumulated at 10 times higher levels than NP loaded with 17R-RvD1. There was a trend toward decreased CD45 immunostaining in vessels treated with NP containing benzo-RvD1 (0.76 ± 0.38 cells/mm2 vs 122.1 ± 22.26 cells/mm2; P = .06). There were no significant differences in early arterial inflammatory and cytokine gene expression by reverse transcription-polymerase chain reaction. ConclusionsTF-targeting peptides enhanced NP-mediated delivery of SPM to injured artery. TF-targeted delivery of SPMs may be a promising therapeutic approach to attenuate the vascular injury response.

Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases

BackgroundThis study examined neuropathological findings of patients who died following hospitalization in an intensive care unit with SARS-CoV-2.MethodsData originate from 20 decedents who underwent brain autopsy followed by ex-vivo imaging and dissection. Systematic neuropathologic examinations were performed to assess histopathologic changes including cerebrovascular disease and tissue injury, neurodegenerative diseases, and inflammatory response. Cerebrospinal fluid (CSF) and fixed tissues were evaluated for the presence of viral RNA and protein.ResultsThe mean age-at-death was 66.2 years (range: 26–97 years) and 14 were male. The patient’s medical history included cardiovascular risk factors or diseases (n = 11, 55%) and dementia (n = 5, 25%). Brain examination revealed a range of acute and chronic pathologies. Acute vascular pathologic changes were common in 16 (80%) subjects and included infarctions (n = 11, 55%) followed by acute hypoxic/ischemic injury (n = 9, 45%) and hemorrhages (n = 7, 35%). These acute pathologic changes were identified in both younger and older groups and those with and without vascular risk factors or diseases. Moderate-to-severe microglial activation were noted in 16 (80%) brains, while moderate-to-severe T lymphocyte accumulation was present in 5 (25%) brains. Encephalitis-like changes included lymphocytic cuffing (n = 6, 30%) and neuronophagia or microglial nodule (most prominent in the brainstem, n = 6, 30%) were also observed. A single brain showed vasculitis-like changes and one other exhibited foci of necrosis with ball-ring hemorrhages reminiscent of acute hemorrhagic leukoencephalopathy changes. Chronic pathologies were identified in only older decedents: 7 brains exhibited neurodegenerative diseases and 8 brains showed vascular disease pathologies. CSF and brain samples did not show evidence of viral RNA or protein.ConclusionsAcute tissue injuries and microglial activation were the most common abnormalities in COVID-19 brains. Focal evidence of encephalitis-like changes was noted despite the lack of detectable virus. The majority of older subjects showed age-related brain pathologies even in the absence of known neurologic disease. Findings of this study suggest that acute brain injury superimposed on common pre-existing brain disease may put older subjects at higher risk of post-COVID neurologic sequelae.

Autoimmune activation and hypersensitization of the AT1 and ETA receptors contributes to vascular injury in scleroderma renal crisis.

Scleroderma renal crisis (SRC) is a rare vascular complication of systemic sclerosis with substantial risks for end-stage renal disease and premature death. Activating autoantibodies (Abs) targeting the angiotensin II type 1 (AT1R) and the endothelin-1 type A receptor (ETAR) have been identified as predictors for SRC. Here, we sought to determine their pathogenic significance for acute renal vascular injury potentially triggering kidney failure and malignant hypertension. IgG from patients with SRC was studied for AT1R and ETAR dependent biologic effects on isolated rat renal interlobar arteries and vascular cells including contraction, signalling and mechanisms of receptor activation. In myography experiments, patient IgG exerted vasoconstriction sensitive to inhibition of AT1R and ETAR. This relied on MEK-ERK signalling indicating functional relevance of anti-AT1R and anti-ETAR Abs. The contractile response to angiotensin II and endothelin-1 was amplified by patient IgG containing anti-AT1R and anti-ETAR Abs with substantial crosstalk between both receptors implicating autoimmune receptor hypersensitization. Co-immunoprecipitation experiments indicated heterodimerization between both receptor types which may enable the observed functional interrelation by direct structural interactions. We provide experimental evidence that agonistic Abs may contribute to SRC. This effect is presumably related to direct receptor stimulation and additional allosteric effects, at least in heterodimeric receptor constellations. Novel therapies targeted at autoimmune hyperactivation of AT1R and ETAR might improve outcomes in severe cases of SRC.

Damage of the great vessels - principles of medical care

Modern aspects of etiology, pathogenesis, clinic, diagnosis and surgical treatment of vascular injuries of the extremities are considered. The surgical tactics in acute vascular injury are covered in detail in practical terms.