Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

Vascular inflammation is a hallmark of both primary systemic vasculitis and atherosclerosis. As such, cardiovascular events are common in patients with vasculitis and likely due to both direct vascular inflammation and accelerated atherosclerosis. Direct cardiac involvement is possible in all vasculitides, though more commonly described in Takayasu arteritis, polyarteritis nodosa, and eosinophilic granulomatosis with polyangiitis. Accelerated atherosclerosis has been described in Takayasu arteritis and antineutrophil cytoplasmic antibody-associated vasculitis, though there remains a paucity of data in other forms of vasculitis. Multiple screening and management approaches for cardiovascular risk in people with vasculitis have been proposed, though evidence-based guidelines are lacking. In this review, we discuss the latest evidence in epidemiology, mechanisms, and screening for atherosclerosis in patients with primary systemic vasculitides.

Background: Sepsis is featured as a systemic inflammation and thrombosis induced by infection. TGF-β (transforming growth factor-β) 1 is mainly secreted from platelets and plays a role in immune response and inflammation. Whether platelet-derived TGF-β1 participates in sepsis remains unclear. This study intends to investigate its role in sepsis in mice.

Methods: Platelet-specific TGF-β1 knockout mice received cecal ligation and puncture surgery to induce sepsis followed by the analysis of survival time, platelets number, pathology changes of lung and liver, liver function, the recruitment of platelets, neutrophils and monocytes, and neutrophil extracellular traps' formation. In addition, adoptive transfer of wild-type platelets into platelet-specific TGF-β1 knockout mice was performed to further evaluate the role of TGF-β1 in the pathogenesis of sepsis.

Results: TGF-β1 level was gradually increased in the lung during the progress of sepsis, and platelets are the major source of the elevated TGF-β1 level in the lung after sepsis. Deficiency of platelet-derived TGF-β1 prolonged the survival of sepsis mice, inhibited the drop of platelet number and bacterial growth, impaired the thrombus formation in the lung and liver, and improved liver function. In addition, platelet TGF-β1 deficiency also decreased the recruitment of neutrophils and monocytes to the lung and impaired neutrophil extracellular trap formation. However, the adoptive transfer of normal platelets to platelet-specific TGF-β1 knockout mice significantly reduced the number of circulating platelets, increased thrombosis in the lung and liver, and promoted the neutrophil extracellular trap formation.

Conclusions: Deficiency of platelet-derived TGF-β1 inhibits septic thrombosis and prolongs survival time, indicating that it might be a novel therapeutic target for the treatment of sepsis.

Background: Andexanet alfa (andexanet) is the only Food and Drug Administration-approved antidote for direct FXa (factor Xa) inhibitors but has been reported to cause resistance to unfractionated heparin (UFH). This has delayed anticoagulation for procedures requiring cardiopulmonary bypass. The mechanism, andexanet and UFH dose dependence, and thrombotic risk of andexanet-associated heparin resistance are unknown.

Methods: The effect of andexanet in vitro was determined using activated clotting times and thromboelastography. Ex vivo cardiopulmonary bypass circuits were used to determine whether andexanet impaired anticoagulation for extracorporeal circulation. Kinetics of AT (antithrombin) inhibition of FXa and thrombin were measured in the presence of andexanet. Equilibrium modeling and thrombin generation assay validation were used to predict the role of andexanet, AT, and UFH concentrations in andexanet-associated heparin resistance.

Results: Andexanet prevented UFH-mediated prolongation of activated clotting times and thromboelastography times. At lower concentrations of andexanet, heparin resistance could be overcome with suprapharmacologic doses of UFH, but not at higher andexanet concentrations. Andexanet rendered standard doses of UFH inadequate to prevent circuit thrombosis, and suprapharmacologic UFH doses were only partially able to overcome this. Scanning electron microscopy demonstrated coagulation activation in circuits. Andexanet prevented UFH enhancement of AT-mediated inhibition of FXa and thrombin. Equilibrium modeling and thrombin generation assay validation demonstrated that andexanet creates a triphasic equilibrium with UFH and AT: initial UFH unresponsiveness, normal UFH responsiveness when andexanet is depleted, and finally AT depletion. Sufficient cardiopulmonary bypass heparinization can only occur at low therapeutic andexanet doses and normal AT levels. Higher andexanet doses or AT deficiency may require high UFH doses and potentially AT supplementation.

Conclusions: Andexanet causes heparin resistance due to redistribution of UFH-bound AT. If andexanet cannot be avoided before heparinization and direct thrombin inhibitors are undesirable, our in vitro study suggests excess UFH should be considered as a potential strategy before AT supplementation.

Climate change involves a shift in earth's climate indicators over extended periods of time due to human activity. Anthropogenic air pollution has resulted in trapping heat, contributing to global warming, which contributes to worsening air pollution through facilitating oxidizing of air constituents. It is becoming more evident that the effects of climate change, such as air pollution and ambient temperatures, are interconnected with each other and other environmental factors. While the relationship between climate change components and cardiovascular disease is well documented in the literature, their interaction with one another along with individuals' biological and social risk factors is yet to be elucidated. In this review, we summarize that pathophysiological mechanisms by ambient temperatures directly affect cardiovascular health and describe the most vulnerable subgroups, defined by age, sex, race, and socioeconomic factors. Finally, we provide guidance on the importance of integrating climate, environmental, social, and health data into common platforms to inform researchers and policies.

Background: Pharmacological inhibition of megalin (also known as LRP2 [low-density lipoprotein receptor-related protein-2]) attenuates atherosclerosis in hypercholesterolemic mice. Since megalin is abundant in renal proximal tubule cells (PTCs), the purpose of this study was to determine whether PTC-specific deletion of megalin reduces hypercholesterolemia-induced atherosclerosis in mice.

Methods: Female Lrp2 f/f mice were bred with male Ndrg1-Cre ERT2 +/0 mice to develop PTC-LRP2 +/+ and PTC-LRP2 -/- littermates. To study atherosclerosis, all mice were bred to an LDL (low-density lipoprotein) receptor -/- background and fed a Western diet to induce atherosclerosis.

Results: PTC-specific megalin deletion did not attenuate atherosclerosis in LDL receptor -/- mice in either sex. Serendipitously, we discovered that PTC-specific megalin deletion led to interstitial infiltration of CD68+ cells and tubular atrophy. The pathology was only evident in male PTC-LRP2 -/- mice fed a Western diet but not in mice fed a normal laboratory diet. Renal pathologies were also observed in male PTC-LRP2 -/- mice in an LDL receptor +/+ background fed the same Western diet, demonstrating that the renal pathologies were dependent on diet and not on hypercholesterolemia. In contrast, female PTC-LRP2 -/- mice had no apparent renal pathologies. In vivo multiphoton microscopy demonstrated that PTC-specific megalin deletion dramatically diminished ALB (albumin) accumulation in PTCs within 10 days of Western diet feeding. RNA-sequencing analyses demonstrated the upregulation of inflammation-related pathways in the kidney.

Conclusions: PTC-specific megalin deletion does not affect atherosclerosis but leads to tubulointerstitial nephritis in mice fed a Western diet, with severe pathologies in male mice.

Background: Coronary artery disease (CAD) is a complex, heterogeneous disease with distinct etiological mechanisms. These different etiologies may give rise to multiple subtypes of CAD that could benefit from alternative preventions and treatments. However, so far, there have been no systematic efforts to predict CAD subtypes using clinical and genetic factors.

Methods: Here, we trained and applied statistical models incorporating clinical and genetic factors to predict CAD subtypes in 26 036 patients with CAD in the UK Biobank. We performed external validation of the UK Biobank models in the US-based All of Us cohort (8598 patients with CAD). Subtypes were defined as high versus normal LDL (low-density lipoprotein) levels, high versus normal Lpa (lipoprotein A) levels, ST-segment-elevation myocardial infarction versus non-ST-segment-elevation myocardial infarction, occlusive versus nonocclusive CAD, and stable versus unstable CAD. Clinical predictors included levels of ApoA, ApoB, HDL (high-density lipoprotein), triglycerides, and CRP (C-reactive protein). Genetic predictors were genome-wide and pathway-based polygenic risk scores (PRSs).

Results: Results showed that both clinical-only and genetic-only models can predict CAD subtypes, while combining clinical and genetic factors leads to greater predictive accuracy. Pathway-based PRSs had higher discriminatory power than genome-wide PRSs for the Lpa and LDL subtypes and provided insights into their etiologies. The 10-pathway PRS most predictive of the LDL subtype involved cholesterol metabolism. Pathway PRS models had poor generalizability to the All of Us cohort.

Conclusions: In summary, we present the first systematic demonstration that CAD subtypes can be distinguished by clinical and genomic risk factors, which could have important implications for stratified cardiovascular medicine.

Background: Lymphangiogenesis is believed to be a protective response in the setting of multiple forms of kidney injury and mitigates the progression of interstitial fibrosis. To augment this protective response, promoting kidney lymphangiogenesis is being investigated as a potential treatment to slow the progression of kidney disease. As injury-related lymphangiogenesis is driven by signaling from the receptor VEGFR3 (vascular endothelial growth factor receptor 3) in response to the cognate growth factor VEGF (vascular endothelial growth factor)-C released by tubular epithelial cells, this signaling pathway is a candidate for future kidney therapeutics. However, the consequences to kidney development and function to targeting this signaling pathway remain poorly defined.

Methods: We generated a new mouse model expressing Vegfc under regulation of the nephron progenitor Six2Cre driver strain (Six2Vegfc). Mice underwent a detailed phenotypic evaluation. Whole kidneys were processed for histology and 3-dimensional imaging.

Results: Six2Vegfc mice had reduced body weight and kidney function compared with littermate controls. Six2Vegfc kidneys demonstrated large peripelvic fluid-filled lesions with distortion of the pelvicalcyceal system which progressed in severity with age. Three-dimensional imaging showed a 3-fold increase in total cortical vascular density. Histology confirmed a substantial increase in LYVE1+ (lymphatic vessel endothelial hyaluronan receptor-1)/PDPN+ (podoplanin)/VEGFR3+ lymphatic capillaries extending alongside EMCN+ (endomucin) peritubular capillaries. There was no change in EMCN+ peritubular capillary density.

Conclusions: Kidney lymphatic density was robustly increased in the Six2Vegfc mice. There were no changes in peritubular blood capillary density despite these endothelial cells also expressing VEGFR3. The model resulted in malformation of the lymphatic hilar plexus, resulting in severe hydronephrosis that resembled a human condition termed renal lymphangiectasia. This study defines the vascular consequences of augmenting VEGFC signaling during kidney development and provides new insight into human renal lymphatic malformations.

Background: The protease thrombin, which elicits multiple physiological and pathological effects on vascular endothelial cells (ECs), can signal through PARs (protease-activated receptors) 1 and 4. PAR1 is a high-affinity thrombin receptor known to signal on ECs, whereas PAR4 is a low-affinity thrombin receptor, and evidence for its expression and function on ECs is mixed. This study aims to exploit the high levels of thrombin generation and hepatic vascular dysfunction that occur during acetaminophen (APAP) overdose to determine (1) whether hepatic endothelial PAR4 is a functional receptor, and (2) the endothelial-specific functions for PAR1 and PAR4 in a high thrombin and pathological setting.

Methods: We generated mice with conditional deletion of Par1/Par4 in ECs and overdosed them with APAP. Hepatic vascular permeability, erythrocyte accumulation in the liver, thrombin generation, and liver function were assessed following overdose. Additionally, we investigated the expression levels of endothelial PARs and how they influence transcription in APAP-overdosed liver ECs using endothelial translating ribosome affinity purification followed by next-generation sequencing.

Results: We found that mice deficient in high-expressing endothelial Par1 or low-expressing Par4 had equivalent reductions in APAP-induced hepatic vascular instability, although mice deficient for both receptors had lower vascular permeability at an earlier timepoint after APAP overdose than either of the single mutants. Additionally, mice with loss of both endothelial Par1 and Par4 had reduced thrombin generation after APAP overdose, suggesting decreased hypercoagulability. Last, we found that endothelial PAR1-but not PAR4-can regulate transcription in hepatic ECs.

Conclusions: Low-expressing PAR4 can react similarly to high-expressing PAR1 in APAP-overdosed hepatic ECs, demonstrating that PAR4 is a potent thrombin receptor. Additionally, these receptors are functionally redundant but act divergently in their expression and ability to influence transcription in hepatic ECs.