Thoracic Endovascular Repair for Aortic Arch Pathologies with Surgeon Modified Fenestrated Stent Grafts: A Multicentre Retrospective Study.

OBJECTIVE: To evaluate the outcome of thoracic endovascular repair (TEVAR) for aortic arch pathologies with surgeon modified fenestrated stent grafts. METHODS: A multicentre, retrospective study consisting of consecutive patients from seven centres treated with surgeon modified fenestrated stent grafts for aortic arch pathologies was conducted. A technique to align fenestrations and supra-aortic vessels was applied. Rates of technical success, mortality, complications, and re-interventions were evaluated. RESULTS: Between February 2016 and January 2020, 513 consecutive patients with aortic arch pathologies received TEVAR with surgeon modified fenestrated stent grafts. The technical success rate was 98.6% (n = 506). In total, 626 fenestrations were created to revascularise 684 branch arteries of the aortic arch. There were 13 deaths and 15 re-interventions within 30 days of the operation. The estimated clinical success rate at 30 days was 94.4% (95% confidence interval [CI] 92.4 - 96.4), the estimated survival at 30 days was 97.5% (95% CI 96.1 - 98.9), and the estimated freedom from re-intervention at 30 days was 97.1% (95% CI 95.7 - 98.5). The median follow up was 27 (interquartile range 13 - 31) months. During follow up, there were five aortic related deaths, three non-aortic related deaths, and four deaths of unknown cause. Eighteen patients underwent re-intervention. The estimated clinical success rate at 24 months was 88.2% (95% CI 85.5 - 91.0), the estimated survival at 24 months was 94.9% (95% CI 92.7 - 97.1), and the estimated freedom from re-intervention at 24 months was 93.1% (95% CI 91.0 - 95.3). In total, 18 cases of stroke were recorded, including 12 within 30 days and six during follow up; six cases of retrograde type A aortic dissection were recorded, including five within 30 days and one during the follow up. CONCLUSION: TEVAR with surgeon modified fenestrated stent grafts for the treatment of aortic arch pathologies provides acceptable outcomes. Further follow up is required to confirm the benefits of this approach.

Upregulation of MicroRNA-126 Contributes to Endothelial Progenitor Cell Function in Deep Vein Thrombosis via Its Target PIK3R2.

Deep vein thrombosis (DVT) is a common complication of surgery. Endothelial progenitor cells (EPCs) are recruited into resolving venous thrombi. In this report, we investigated the effects of miR-126 on EPCs function and venous thrombus resolution. We demonstrated that overexpression of miR-126 enhanced EPCs' migration and tubulogenic activity in vitro, and promoted EPCs' homing and thrombus resolving in vivo. Moreover, we identified that miR-126 directly targeted PIK3R2 and affected PI3K/Akt signaling axis. Overall, our findings demonstrated that miR-126 promoted EPCs function through suppressing PIK3R2 expression and modulation of miR-126 may represent a potential therapeutic intervention for treating DVT.

Immediate and middle term outcome of symptomatic spontaneous isolated dissection of the superior mesenteric artery.

PURPOSE: Spontaneous isolated dissection of the superior mesenteric artery (SIDSMA) is a rare but fatal condition. Herein, we report the therapeutic outcome of a contemporary series of 12 patients with SIDSMA who were treated with conservative, anticoagulation, or endovascular therapy. METHODS: Revascularization was measured according to recanalization of the primary arterial occlusive lesion and reperfusion was measured by flow through the occluded vessel. Pain was evaluated by using the visual analog scale (VAS) at admission and at each follow-up visit. RESULTS: Type I SIDSMA was seen in 3 (25%) patients, type IIa in 4 (33.3%) patients, and type IIb in 5 (41.7%) patients. No patient had type III SIDSMA. The false lumens were patent in 6 (50%) patients. Partial thrombosis in the false lumen was demonstrated in CT scans in 5 (41.7%) patients and total thrombosis in 1 (8.3%) patient. Four (33.3%) patients received conservative therapy, and 2 (16.7%) patients received anticoagulation therapy. All six patients resumed normal blood flow in the SMA. The remaining six patients received endovascular stenting. After stent placement, excellent distal blood flow was restored. Abdominal pain was completely resolved in all patients except in one patient. No complications associated with SMA dissection occurred. CONCLUSION: If bowel perfusion is not compromised and the SMA aneurysm is not likely to rupture in patients with a symptomatic SIDSMA, conservative, or anticoagulation therapy can be considered. If patient has sustained intestinal ischemic symptoms, and severe compression of the true lumen, or dissecting aneurysm likely to rupture, endovascular therapy, or surgery should be adopted.

Outcome of endovascular treatment in postthrombotic syndrome.

BACKGROUND: The postthrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT) that is characterized by leg swelling and ulceration. METHODS: Sixty-seven cases of PTS underwent attempted endovascular treatment with success in 63 between June 2005 and June 2012. Thirty-six cases underwent endovascular treatment only and 18 cases combined with temporary femoral arteriovenous fistula, 5 cases great saphenous vein ligation and stripping whereas 4 cases with communicating branch ligation around ulcers. RESULTS: Stenting was successfully performed in 63 of 67 patients. The technical success rate was 94% with no mortality. Fifty-eight cases were followed up from 1 to 84 months. Stent occlusion or restenosis occurred in 17 patients. The primary and secondary patency rates were 87.9% and 93.1%, respectively, at 12 months and 70.7% and 82.8%, respectively, at 36 months. CONCLUSIONS: Endovascular treatment of PTS is safe and effective. It can alleviate symptoms and prevent further deterioration of patients with PTS.

[Therapy of catheter-directed thrombolysis for inferior vena cava thrombosis after filter implantation].

OBJECTIVE: To evaluate the efficacy and safety of catheter-directed thrombolysis (CDT) in treating with inferior vena cava (IVC) thrombosis after filter implantation. METHODS: A retrospective analysis of 13 patients with IVC thrombosis after filter implantation was conducted at our institution from June 2009 to June 2012. A total of 26 lower extremities were involved.IVC filters were implanted via right internal jugular vein. Then CDT was performed through small saphenous vein, popliteal vein or femoral vein. The dosage of urokinase was 0.6-1 million/day. The occlusive segment in IVC was managed with percutaneous transluminal angioplasty (PTA) and stenting. RESULTS: The obstructed IVC was re-opened after CDT in 11 cases. The average CDT time was 8.3 (7-13) days. PTA (n = 2) and stenting (n = 1) were performed. A total of 4 retrievable filters were planted and retrieved later successfully.No severe complications occurred. During the follow-ups, no clinically detetable sighs of pulmonary embolism were observed. CONCLUSION: CDT is effective, safe and feasible in the treatment of IVC thrombosis after filter implantation.

miR-590-3p Overexpression Improves the Efficacy of hiPSC-CMs for Myocardial Repair.

Recent evidence demonstrates that low engraftment rates limit the efficacy of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for cardiac repair after myocardial infarction. In this study, we attempted to overcome this limitation by enhancing the proliferative capacity of transplanted hiPSC-CMs. We found that miR-590-3p overexpression increased the proliferative capacity of hiPSC-CMs. miR-590-3p overexpression increased the number of engrafted cells and had a higher efficacy for myocardial repair than control cells. Moreover, we confirmed the safety of using miR-590-3p-overexpressing hiPSC-CMs in pig hearts. These results indicated that miR-590-3p overexpression stimulated hiPSC-CM cell cycle re-entry to induce cell proliferation and increased the therapeutic efficacy in MI.

[Endovascular therapy of superior mesenteric artery embolism].

OBJECTIVE: To explore the safety and immediate efficacy of endovascular treatment for superior mesenteric artery embolism. METHODS: From November 2007 to October 2012, 18 cases of superior mesenteric artery embolism were treated by thrombus extraction and/or catheter-directed thrombolysis. There were 13 males and 5 females with an age range of 44-91 years. The concurrent conditions included atrial fibrillation (n = 8) and rheumatic valve disease (n = 3). All diagnoses were made with abdominal enhanced computed tomography (CT) examination. Embolism was predominantly located at 3 to 10 cm away from opening. The procedures included thrombus extraction plus system thrombosis (n = 3), thrombus extraction and catheter-directed thrombolysis (n = 6), catheter-directed thrombolysis (n = 5) and thrombus extraction, catheter-directed thrombolysis and PTA (n = 2). RESULTS: The technical success rate was 100%. Two cases had new embolism in popliteal artery. Another case with peritoneal irritation syndrome died after automatic discharge. The other 17 patients obtained satisfactory results and were followed up after 6 months by color Doppler ultrasound or abdominal enhanced CT. It showed that superior mesenteric arteries were unobstructed, but local stenosis occurred in 2 cases. CONCLUSION: Endovascular interventional therapy is both safe and efficacious in the treatment of superior mesenteric artery embolization. And its immediate effect is satisfactory.

Novel bilayer cell patch combining epidermal stem cells and angiogenic adipose stem cells for diabetic wound healing.

Diabetic foot ulcer (DFU) is one of the most severe complications in patients with diabetes. However, the development of a promising therapeutic strategy for DFU is still challenging. In this article, we demonstrate a novel bilayer cell patch, and its therapeutic effects on diabetic wound healing have been systematically investigated. The experimental results revealed that diabetes mellitus exosomes (DM-Exos) could inhibit wound healing in normal C57/B6 mice. We identified three microRNAs (miRs) including miR-15a, miR-16, and miR-214 as anti-angiogenesis factors in DM-Exos. Furthermore, angiogenic-modified adipose stem cells (ADSCs, transfected with antagomiR-15a, antagomiR-16, and antagomiR-214) were found to enhance the angiogenesis ability of human umbilical vein endothelial cells (HUVECs) by co-culture. In addition, our findings exhibited that the bilayer cell patch combining epidermal stem cells (EpSCs) and angiogenic-modified ADSCs transplantation could promote diabetic wound healing through enhancing angiogenesis and re-epithelization. These findings illustrate that the novel bilayer cell patch has great potential in diabetic wound healing.

Netrin-1 Monoclonal Antibody-Functionalized Nanoparticle Loaded with Metformin Prevents the Progression of Abdominal Aortic Aneurysms.

Background: Abdominal aortic aneurysms (AAAs) are a global health and economic burden. Therapeutic strategies to inhibit the progression of AAAs are currently lacking. Recently, the therapeutic effect of metformin on aneurysms has attracted considerable interest. However, the unfavorable pharmacokinetic properties of metformin limit its feasibility for AAA treatment. Methods and Results: We constructed a metformin-loaded netrin-1-responsive AAA-targeted nanoparticle (Tgt-NP-Met) for AAA management. Evaluation of the therapeutic effect of Tgt-NP-Met was performed by in vitro and in vivo experiments. Our results showed that the binding of netrin-1 monoclonal antibodies enhanced the AAA-targeting capability of nanoparticles (NPs). Moreover, Tgt-NP-Met administration prevented AAA development and reduced the aneurysm diameter in apolipoprotein E (ApoE)-deficient (ApoE-/-) mice that received continuous infusion of angiotensin II. Furthermore, metformin prevented AAA progression by inhibiting the transformation of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a synthetic phenotype, which is mediated by macrophage infiltration and activation. Conclusion: Our findings identify metformin as a functional suppressor for macrophage-mediated phenotypic transformation of VSMCs and Tgt-NP-Met as an efficient therapeutic strategy for AAA management.

Aortic smooth muscle TRPV4 channels regulate vasoconstriction in high salt-induced hypertension.

Recent studies have focused on the contribution of vascular endothelial transient receptor potential vanilloid 4 (TRPV4) channels to hypertension. However, in hypertension, TRPV4 channels in vascular smooth muscle remain unexplored. In the present study, we performed wire myograph experiments in isolated aortas from endothelial cell specific TRPV4 channel knockout (TRPV4EC-/-) mice to demonstrate that GSK1016790A (a specific TRPV4 channel agonist) triggered aortic smooth muscle-dependent contractions from mice on a normal-salt diet, and the contractions were enhanced in high-salt diet (HSD) mice. Intracellular Ca2+ concentration ([Ca2+]i) and Ca2+ imaging assays showed that TRPV4-induced [Ca2+]i was significantly higher in aortic smooth muscle cells (ASMCs) from HSD-induced hypertensive mice, and application of an inositol trisphosphate receptor (IP3R) inhibitor markedly attenuated TRPV4-induced [Ca2+]i. IP3R2 expression was enhanced in ASMCs from HSD-induced hypertensive mice and the contractile response induced by TRPV4 was inhibited by the IP3R inhibitor. Whole-transcriptome analysis by RNA-seq and western blot assays revealed the involvement of interferon regulatory factor 7 (IRF7) in TRPV4-IRF7-IP3R2 signaling in HSD-induced hypertension. These results suggested that TRPV4 channels regulate smooth muscle-dependent contractions in high salt-induced hypertension, and this contraction involves increased [Ca2+]i, IP3R2, and IRF7 activity. Our study revealed a considerable effect of TRPV4 channels in smooth muscle-dependent contraction in mice during high-salt induced hypertension.

Evaluation of Circulating Endothelial Progenitor Cells in Abdominal Aortic Aneurysms after Endovascular Aneurysm Repair.

Background and Objectives: Circulating endothelial progenitor cells (EPCs) participate in vascular repair and predict cardiovascular outcomes. The aim of this study was to investigate the correlation between EPCs and abdominal aortic aneurysms (AAAs). Methods and Results: Patients (age 67±9.41 years) suffering from AAAs (aortic diameters 58.09±11.24 mm) were prospectively enrolled in this study. All patients received endovascular aneurysm repair (EVAR). Blood samples were taken preoperatively and 14 days after surgery from patients with aortic aneurysms. Samples were also obtained from age-matched control subjects. Circulating EPCs were defined as those cells that were double positive for CD34 and CD309. Rat models of AAA formation were generated by the peri-adventitial elastase application of either saline solution (control; n=10), or porcine pancreatic elastase (PPE; n=14). The aortas were analyzed using an ultrasonic video system and immunohistochemistry. The levels of CD34＋/CD309＋ cells in the peripheral blood mononuclear cell populations were measured by flow cytometry. The baseline numbers of circulating EPCs (CD34＋/CD309＋) in the peripheral blood were significantly smaller in AAA patients compared with control subjects. The number of EPCs doubled by the 14th day after EVAR. A total of 78.57% of rats in the PPE group (11/14) formed AAAs (dilation ratio ＞150%). The numbers of EPCs from defined AAA rats were significantly decreased compared with the control group. Conclusions: EPC levels may be useful for monitoring abdominal aorta aneurysms and rise after EVAR in patients with aortic aneurysms, and might contribute to the rapid endothelialization of vessels.

Defects in conformal crystals: Discrete versus continuous disclination models.

We study the relationship between topological defect formation and ground-state 2D packings in a model of repulsions in external confining potentials. Specifically we consider screened 2D Coulombic repulsions, which conveniently parameterizes the effects of interaction range, but also serves as simple physical model of confined, parallel arrays of polyelectrolyte filaments or vortices in type II superconductors. The countervailing tendencies of repulsions and confinement to, respectively, spread and concentrate particle density leads to an energetic preference for nonuniform densities in the clusters. Ground states in such systems have previously been modeled as conformal crystals, which are composed of locally equitriangular packings whose local areal densities exhibit long-range gradients. Here we assess two theoretical models that connect the preference for nonuniform density to the formation of disclination defects, one of which assumes a continuum distributions of defects, while the second considers the quantized and localized nature of disclinations in hexagonal conformal crystals. Comparing both theoretical descriptions to numerical simulations of discrete particles clusters, we study the influence of interaction range and confining potential on the topological charge, number, and distribution of defects in ground states. We show that treating disclinations as continuously distributable well captures the number of topological defects in the ground state in the regime of long-range interactions, while as interactions become shorter range, it dramatically overpredicts the growth in total defect charge. Detailed analysis of the discretized defect theory suggests that that failure of the continuous defect theory in this limit can be attributed to the asymmetry in the preferred placement of positive vs negative disclinations in the conformal crystal ground states, as well as a strongly asymmetric dependence of self-energy of disclinations on sign of topological charge.

Adult Cardiomyocyte Proliferation: a New Insight for Myocardial Infarction Therapy.

Myocardial infarction leads to cardiomyocyte loss, ensuing ventricular pathological remodeling, dramatic impairment of cardiac function, and ultimately heart failure. Unfortunately, the existing therapeutical treatments cannot directly replenish the lost myocytes in the injured myocardium and the long-term prognosis of heart failure after myocardial infarction remains poor. Growing investigations have demonstrated that the adult mammalian cardiomyocytes possess very limited proliferation capacity, and that was not enough to restore the injured heart. Recently, many studies were targeting to promote cardiomyocyte proliferation via inducing cardiomyocyte cell cycle re-entry for cardiac repair after myocardial infarction. Indeed, these results showed it is a feasible way to stimulate terminally differentiated cardiomyocyte proliferation. Here, we reviewed the major mechanisms and the potential targets for stimulating mammalian adult cardiomyocyte proliferation specifically. This will provide a new therapeutic strategy for the clinical treatment of myocardial infarction by activating the endogenous regeneration. Graphical abstract.

ADGRG1 enriches for functional human hematopoietic stem cells following ex vivo expansion-induced mitochondrial oxidative stress.

The heterogeneity of human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) under stress conditions such as ex vivo expansion is poorly understood. Here, we report that the frequencies of SCID-repopulating cells were greatly decreased in cord blood (CB) CD34+ HSCs and HPCs upon ex vivo culturing. Transcriptomic analysis and metabolic profiling demonstrated that mitochondrial oxidative stress of human CB HSCs and HPCs notably increased, along with loss of stemness. Limiting dilution analysis revealed that functional human HSCs were enriched in cell populations with low levels of mitochondrial ROS (mitoROS) during ex vivo culturing. Using single-cell RNA-Seq analysis of the mitoROS low cell population, we demonstrated that functional HSCs were substantially enriched in the adhesion GPCR G1-positive (ADGRG1+) population of CD34+CD133+ CB cells upon ex vivo expansion stress. Gene set enrichment analysis revealed that HSC signature genes including MSI2 and MLLT3 were enriched in CD34+CD133+ADGRG1+ CB HSCs. Our study reveals that ADGRG1 enriches for functional human HSCs under oxidative stress during ex vivo culturing, which can be a reliable target for drug screening of agonists of HSC expansion.

Long noncoding RNA DUXAP8 regulates proliferation and apoptosis of ovarian cancer cells via targeting miR-590-5p.

The aim of this study is to investigate the effect of lncRNA DUXAP8 on proliferation and apoptosis of ovarian cancer cells, and to explore its potential mechanism. DUXAP8 interfering and overexpressing cell lines were constructed and the cell proliferation and apoptosis were tested. Hematoxylin-eosin, TdT-mediated dUTP nick end labeling, and immunohistochemistry were used to detect the effect of DUXAP8 on the ability of tumor formation. Quantitative real-time polymerase chain reaction and western blot were used to detect the mRNA and protein expression of miR-590-5p and YAP1, respectively. Dual luciferase assay was used to determine the target relationship between DUXAP8, miR-590-5p, and YAP1. DUXAP8 interference and miR-590-5p down-regulated cell lines were further constructed. Compared with normal ovarian cells, the expression of DUXAP8 in ovarian cancer cells was significantly increased, while the expression of miR-590-5p was decreased (p < 0.05). After DUXAP8 interference, cell proliferation and colony formation were decreased, and apoptosis was increased. The results of in vivo experiment are consistent with the in vitro experiments. The expression of miR-590-5p was up-regulated and the expression of YAP1 was decreased after DUXAP8 interference. Moreover, miR590-5p inhibitor can attenuate the effect of DUXAP8 interference on ovarian cancer cells. Taken together, lncRNA DUXAP8 can regulate the proliferation and apoptosis of ovarian cancer cells, and its mechanism may be related to the regulation of YAP1 gene by targeting miR-590-5p.

Self-Assembling Peptide-Based Hydrogels in Angiogenesis.

Ischemic diseases, especially in the heart and the brain, have become a serious threat to human health. Growth factor and cell therapy are emerging as promising therapeutic strategies; however, their retention and sustainable functions in the injured tissue are limited. Self-assembling peptide (SAP)-based hydrogels, mimicking the extracellular matrix, are therefore introduced to encapsulate and controllably release cells, cell-derived exosomes or growth factors, thus promoting angiogenesis and tissue recovery after ischemia. We will summarize the classification, composition and structure of SAPs, and the influencing factors for SAP gelation. Moreover, we will describe the functionalized SAPs, and the combinatorial therapy of cells, exosomes or growth factors with functionalized SAPs for angiogenic process as well as its advantage in immunogenicity and injectability. Finally, an outlook on future directions and challenges is provided.

Downregulation of MicroRNA-206 Alleviates the Sublethal Oxidative Stress-Induced Premature Senescence and Dysfunction in Mesenchymal Stem Cells via Targeting Alpl.

Bone marrow-derived mesenchymal stem cells (MSCs) have shown great promise in tissue engineering and regenerative medicine; however, the regenerative capacity of senescent MSCs is greatly reduced, thus exhibiting limited therapy potential. Previous studies uncovered that microRNA-206 (miR-206) could largely regulate cell functions, including cell proliferation, survival, and apoptosis, but whether miR-206 is involved in the senescent process of MSCs remains unknown. In this study, we mainly elucidated the effects of miR-206 on MSC senescence and the underlying mechanism. We discovered that miR-206 was upregulated in the senescent MSCs induced by H2O2, and abrogation of miR-206 could alleviate this tendency. Besides, we determined that by targeting Alpl, miR-206 could ameliorate the impaired migration and paracrine function in MSCs reduced by H2O2. In vivo study, we revealed that inhibition of miR-206 in senescent MSCs could effectively protect their potential for myocardial infarction treatment in a rat MI model. In summary, we examined that inhibition of miR-206 in MSCs can alleviate H2O2-induced senescence and dysfunction, thus protecting its therapeutic potential.

Retraction Note: Endothelial progenitor cell-derived exosomes, loaded with miR-126, promoted deep vein thrombosis resolution and recanalization.

The authors have retracted this article [1] because there is erroneous data in Figure 1C. Flow cytometry results of EPC cell markers CD31 and CD45 could not be replicated. Due to incorrect cell markers, the cells cultured may not have been pure EPCs. Therefore the scientific content of the article is no longer reliable. All authors agree to this retraction.

[Curative effects of extrusive and Fogarty balloon catheter embolectomy in acute femoral vein thrombosis: experiment with rabbits].

OBJECTIVE: To compare the influence extrusive and Fogarty balloon catheter embolectomy on the patency rate of bloodstream and the damage of the wall of vein in acute femoral vein thrombosis. METHODS: Eighty rabbits were randomly divided into 4 groups: Group A (n = 25) undergoing ligation of unilateral femoral to establish acute femoral vein thrombosis model and treated by extrusion of the hind leg muscles 24 h after the operation, Group B (n = 25) treated by Fogarty balloon catheter embolectomy 24 h after establishment of the thrombosis model, Group C (n = 25) undergoing sham operation, and Group D (n = 5) as normal controls.7, 14, and 28 days after the treatment digital subtraction angiography (DSA) was conducted to observe the patency rate of the vessel.1, 4, 7, 14, and 28 days after the treatment specimens of the thrombotic and corresponding sections of the veins were collected from the 4 groups (on days 1 and 7 for Group D) to undergo transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Quantitative reverse transcription and polymerase chain reaction was used to detect the level of tissue thromboplastin (TF). ELISA was used to detect the levels of thromboxane B(2), (TXB(2)) and 6-keto-prostaglandin F1alpha (PGF1alpha). RESULTS: Occlusion was seen in 3 femoral veins of Group B and one femoral vein of Group (P < 0.01), and the other veins were all patent. TEM and SEM showed that the endothelial cell injury was slight in Group A, and aggravated in Group B. TF mRNA expression could be seen 1 day after the treatment in Groups A, B, and C, and peaked on the day 7, and not found in Group D at any time points (all P < 0.01); and the TF mRNA levels at different time points of Group A were all significantly lower than those of Group B (all P < 0.01). The TXB(2) expression levels on days 1 and 7 of Groups A, B, and C were all significantly higher than those of Group D; especially those of Group B (all P < 0.01). The 6-keto-PGF(1)alpha levels on days 1 and 7 of Group D were both significantly higher than those of Groups A, B, and C (all P < 0.01). CONCLUSION: Compared with Fogarty balloon catheter embolectomy, extrusion embolectomy can discard the thrombus more thoroughly and guarantee the patency rate of bloodstream. Both extrusion embolectomy and Fogarty balloon catheter embolectomy, especially the latter, cause damage to the blood vessel endothelium.