Progression Of Vascular Disorders Research Articles

Глазные проявления у больных, перенесших COVID-19 в ранние сроки после операции ФЭК с ИОЛ

Purpose. To study the ocular manifestations in patients with pseudophakia who underwent COVID-19 during the rehabilitation period after surgery. Material and methods. 46 patients with Phaco with implantation of IOL who underwent COVID-19 in the period from 1 week to 2 months after surgery. Of the examined patients, there were 28 men (61%), 18 women (391%). The average age of the patients was 63±1,2 years. Results. In 78% of cases, vascular pathology of the anterior and posterior segments of the eyeball was observed in patients who underwent COVID-19 in the early postoperative period after Phaco with implantation of IOL. Conclusions. The main ocular symptoms from the anterior segment of the eyeball in patients in 17% of cases were the occurrence or intensification of previously existing manifestations of the «dry eye» syndrome, as well as inflammatory phenomena from the anterior part of the uveal tract. From the posterior segment of the eye, in 70% of cases, there was a progression of vascular disorders, as well as the appearance of complications associated with manifestations of hypercoagulation syndrome and systemic vasculopathy. Key words: Covid-19, cataract phacoemulsification, pseudophakia.

TRPC and TRPV Channels' Role in Vascular Remodeling and Disease.

Transient receptor potentials (TRPs) are non-selective cation channels that are widely expressed in vascular beds. They contribute to the Ca2+ influx evoked by a wide spectrum of chemical and physical stimuli, both in endothelial and vascular smooth muscle cells. Within the superfamily of TRP channels, different isoforms of TRPC (canonical) and TRPV (vanilloid) have emerged as important regulators of vascular tone and blood flow pressure. Additionally, several lines of evidence derived from animal models, and even from human subjects, highlighted the role of TRPC and TRPV in vascular remodeling and disease. Dysregulation in the function and/or expression of TRPC and TRPV isoforms likely regulates vascular smooth muscle cells switching from a contractile to a synthetic phenotype. This process contributes to the development and progression of vascular disorders, such as systemic and pulmonary arterial hypertension, atherosclerosis and restenosis. In this review, we provide an overview of the current knowledge on the implication of TRPC and TRPV in the physiological and pathological processes of some frequent vascular diseases.

Abstract 492: Adipolin/C1q/Tnf-related Protein 12 reduces Neointimal Formation And Atherosclerotic Lesion Development By Modulation Of Macrophage Inflammatory Response And Endothelial Cell Function

Objectives: Obesity is causally linked to the progression of vascular disorders including atherosclerosis and post-angioplasty restenosis. Recently, we identified adipolin/C1q/Tnf-related protein 12 as an insulin sensitizing adipokine,which is downregulated in rodent models of obesity. Here, we investigated whether adipolin modulates the development of vascular diseases using loss-of-function genetic manipulations. Methods and Results: Under basal conditions, no significant differences were observed in body weight, organ weights, blood pressure and fasting plasma glucose levels between wild-type (WT) and adipolin-knockout (APL-KO) mice. APL-KO mice exhibited enhanced neointimal thickening after femoral artery injury compared with WT mice, which was accompanied by increased expression levels of pro-inflammatory mediators including tumor necrosis factor (TNF)-α and interleukin (IL)6 in injured vessels. Conversely, systemic administration of adipolin to WT mice using adenoviral vector expression systems ameliorated injury-induced neointimal thickening and inflammatory response. APL-KO mice also showed impaired re-reendothelialization after vascular injury compared with WT mice. Furthermore, adipolin deficiency increased atherosclerotic lesion area in an apolipoprotein E-knockout mouse model, which was accompanied by enhanced inflammatory response in the arterial vessel walls. Treatment of cultured macrophages with recombinant adipolin protein attenuated lipopolysaccharide-stimulated expression of inflammatory mediators, such as TNF-α and IL6. The anti-inflammatory actions of adipolin in macrophages were reversed by inhibition of transforming growth factor-β receptor II (TGF-βRII)/Smad2 signaling. In addition, treatment of human umbilical vein endothelial cells with adipolin protein promoted migratory activity and reduced serum starvation-induced apoptosis. Conclusion: These data suggest that adipolin suppresses injury-induced neointimal formation and atherosclerosis development through its abilities to modulate macrophage inflammatory responses and endothelial cell functions in vascular walls.

Peritoneal dialysis assists residual renal function to maintain glucose tolerance: a prospective observational study

Renal failure can cause the deterioration of glucose metabolism and increase blood glucose fluctuations, which have been reported to be a factor in the progression of vascular disorders. Little information is available on the daily variation in blood glucose levels in patients with end-stage renal disease (ESRD) and peritoneal dialysis (PD). Daily plasma glucose excursion was evaluated by continuous glucose monitoring (CGM) for 24–72 h. Fourteen ESRD patients without type 2 diabetic nephropathy (non-diabetic patients) and six ESRD patients with type 2 diabetic nephropathy (diabetic patients) participated in this study. ESRD patients started PD which were undergone in only the daytime, and not in the night time. As the PD solution, Dianeal®1.5 % PD-2N (1.5 L) was infused intraperitoneally for 3 h three times daily. The patients received standard meals with a total calorie intake of 30 kcal/kg/day and a protein intake of 0.8 g/kg/day before and after initiation of PD. Daily glucose profiles were measured both 2 week before and 1 week after the commencement of PD with CGM system (CGMS). CGMS parameters were compared between before and after the initiation of PD. In non-diabetic patients with ESRD, the maximum glucose concentration (GC) and area under the curve (AUC) of GC >140 mg/dL significantly decreased after PD initiation. In diabetic patients with ESRD, the mean GC, SD, minimum value, AUC of GC >140 mg/dL, and maximum nocturnal GC significantly decreased, while the percentage of nocturnal GC <70 mg/dL markedly increased after PD commencement. In all patients, there was a significant negative correlation between the incidence of hypoglycemia and residual renal function before the initiation of PD and the correlation disappeared after PD initiation. In all patients, the GC range and coefficient of variation were negatively associated with the peritoneal Kt/V value. Residual renal function promotes the maintenance of glucose tolerance in patients with ESRD. Glucose fluctuation improved shortly after initiation of PD, whereas nocturnal hypoglycemia was evident in diabetic patients.

Inhibitory effects of hydroxysafflor yellow A on PDGF‑BB‑induced proliferation and migration of vascular smooth muscle cells via mediating Akt signaling.

The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are key pathological factors in the initiation and progression of vascular disorders, including arteriosclerosis and restenosis following percutaneous coronary intervention (PCI). Hydroxysafflor yellow A (HSYA), the main component of the safflower yellow pigments, has widely been used for the treatment of cardiovascular diseases in traditional Chinese medicine. However, to the best of our knowledge, there are no studies investigating the pharmaceutical effect of HSYA on VSMCs or the underlying molecular mechanism. The present study aimed to investigate the effect of HSYA on platelet‑derived growth factor (PDGF)‑BB‑stimulated VSMC proliferation and migration. HSYA significantly inhibited PDGF‑BB‑stimulated VSMC proliferation and, in response to PDGF‑BB‑stimulation, VSMCs dedifferentiated into a proliferative phenotype. However, HSYA effectively reversed this phenotype switching. In addition, the production of nitrous oxide and cyclic guanosine monophosphate induced by PDGF‑BB was also suppressed by HSYA, and HSYA markedly inhibited PDGF‑BB‑stimulated VSMC migration. Investigation of the molecular mechanism revealed that HSYA inhibited PDGF‑BB‑induced activation of Akt signaling. In addition, HSYA also suppressed PDGF‑BB‑stimulated upregulation of cell cycle related proteins and heme oxygenase‑1. In conclusion, HSYA was able to inhibit PDGF‑BB‑stimulated VSMC proliferation and migration, partially via suppressing PDGF‑BB‑induced Akt signaling activation. Therefore, HSYA may be useful for the prevention and treatment of cardiovascular diseases, including atherosclerosis and restenosis following PCI.

Stem and progenitor cells in biostructure of blood vessel walls

Development of vascular and hematopoietic systems during organogenesis occurs at the same time. During vasculogenesis, a small part of cells does not undergo complete differentiation but stays on this level, "anchored" in tissue structures described as stem cell niches. The presence of blood vessels within tissue stem cell niches is typical and led to identification of niches and ensures that they are functioning. The three-layer biostructure of vessel walls for artery and vein, tunica: intima, media and adventitia, for a long time was defined as a mechanical barrier between vessel light and the local tissue environment. Recent findings from vascular biology studies indicate that vessel walls are dynamic biostructures, which are equipped with stem and progenitor cells, described as vascular wall-resident stem cells/progenitor cells (VW-SC/PC). Distinct zones for vessel wall harbor heterogeneous subpopulations of VW-SC/PC, which are described as "subendothelial or vasculogenic zones". Recent evidence from in vitro and in vivo studies show that prenatal activity of stem and progenitor cells is not only limited to organogenesis but also exists in postnatal life, where it is responsible for vessel wall homeostasis, remodeling and regeneration. It is believed that VW-SC/PC could be engaged in progression of vascular disorders and development of neointima. We would like to summarize current knowledge about mesenchymal and progenitor stem cell phenotype with special attention to distribution and biological properties of VW-SC/PC in biostructures of intima, media and adventitia niches. It is postulated that in the near future, niches for VW-SC/PC could be a good source of stem and progenitor cells, especially in the context of vessel tissue bioengineering as a new alternative to traditional revascularization therapies.

Adipose‐derived factor CTRP9 attenuates vascular smooth muscle cell proliferation and neointimal formation

Obesity is closely associated with the progression of vascular disorders, including atherosclerosis and postangioplasty restenosis. C1q/TNF-related protein (CTRP) 9 is an adipocytokine that is down-regulated in obese mice. Here we investigated whether CTRP9 modulates neointimal hyperplasia and vascular smooth muscle cell (VSMC) proliferation in vivo and in vitro. Left femoral arteries of wild-type (WT) mice were injured by a steel wire. An adenoviral vector expressing CTRP9 (Ad-CTRP9) or β-galactosidase as a control was intravenously injected into WT mice 3 d before vascular injury. Delivery of Ad-CTRP9 significantly attenuated the neointimal thickening and the number of bromodeoxyuridine-positive proliferating cells in the injured arteries compared with that of control. Treatment of VSMCs with CTRP9 protein attenuated the proliferative and chemotactic activities induced by growth factors including platelet-derived growth factor (PDGF)-BB, and suppressed PDGF-BB-stimulated phosphorylation of ERK. CTRP9 treatment dose-dependently increased cAMP levels in VSMCs. Blockade of cAMP-PKA pathway reversed the inhibitory effect of CTRP9 on DNA synthesis and ERK phosphorylation in response to PDGF-BB. The present data indicate that CTRP9 functions to attenuate neointimal formation following vascular injury through its ability to inhibit VSMC growth via cAMP-dependent mechanism, suggesting that the therapeutic approaches to enhance CTRP9 production could be valuable for prevention of vascular restenosis after angioplasty.

Abstract 5806: SRF Protects Brain Endothelial Cells Against Hypoxic Damage

Ischemia resulting from brain vascular disorders is the major cause of stroke. Hypoxia triggers both angiogenesis and apoptosis through the induction of HIF1 α -activated VEGF and the alteration of mitochondrial permeability, respectively. The balance between these two events is crucial to both the progression of vascular disorders and the outcome of injury healing. Our previous study showed that SRF (Serum response factor) is essential to VEGF-induced angiogenesis. This study aimed to determine the roles of SRF in hypoxia-induced brain endothelial cell angiogenesis and apoptosis. Methods : Mouse brain endothelial cells (bEND3) were transfected with either an SRF expressing plasmid, SRF shRNA, or the vehicle (control), and cultured under hypoxic condition (5% CO 2 : 94% N 2 : 1% O 2 ) for 0, 0.5, 2, 6 and 24 hours. Angiogenesis and apoptosis were assessed by 3-D in vitro angiogenesis assay and Annexin V binding assay, respectively. Results : After 30-min hypoxic treatment, SRF mRNA expression was dramatically increased by 54 fold and then gradually declined and returned to normal at 24 hours. SRF protein expression and phosphorylation were also increased by 111±24 % and 74±7 % (both P &lt; 0.01), respectively, after 6-hour hypoxia. Hypoxia also enhanced SRF binding activity to DNA. Forced overexpression of SRF increased hypoxia-induced angiogenesis by 232±15 % (P &lt; 0.01); and knockdown of SRF completely abolished it. After 24-hour hypoxia, 29±4 % of the cells underwent apoptosis; while overexpression of SRF reduced this percentage to 5.7±1 %; and knockdown of SRF increased it to 85±4 % (all P &lt; 0.001). Overexpression of SRF increased Bcl-2/Bax ratio by 23±4 % at baseline and by 167±20 % after 24-hour hypoxia; knockdown of SRF decreased these ratios by 69±3 % and 75±8 %, respectively (all P &lt; 0.01). Knockdown of SRF also increased Bax translocation to mitochondria and Cytochrome C release. Conclusions : Hypoxia triggers SRF activation. Up-regulation of SRF promotes angiogenesis. Down-regulation of SRF sensitizes cells to hypoxia-induced apoptosis. SRF protects against hypoxia-induced apoptosis likely through both direct up-regulation of Bcl-2 and indirect down-regulation of Bax. This research has received full or partial funding support from the American Heart Association, Western States Affiliate (California, Nevada &amp; Utah).

Integration of non-SMAD and SMAD signaling in TGF-β1-induced plasminogen activator inhibitor type-1 gene expression in vascular smooth muscle cells

Overexpression of plasminogen activator inhibitor-1 (SERPINE1, PAI-1), the major physiological inhibitor of pericellular plasmin generation, is a significant causative factor in the progression of vascular disorders (e.g. arteriosclerosis, thrombosis, perivascular fibrosis) as well as a biomarker and a predictor of cardiovascular-disease associated mortality. PAI-1 is a temporal/spatial regulator of pericellular proteolysis and ECM accumulation impacting, thereby, vascular remodeling, smooth muscle cell migration, proliferation and apoptosis. Within the specific context of TGF-beta1-initiated vascular fibrosis and neointima formation, PAI-1 is a member of the most prominently expressed subset of TGF-beta1-induced transcripts. Recent findings implicate EGFR/pp60c-src-->MEK/ERK1/2 and Rho/ROCK-->SMAD2/3 signaling in TGF-beta1-stimulated PAI-1 expression in vascular smooth muscle cells. The EGFR is a direct upstream regulator of MEK/ERK1/2 while Rho/ROCK modulate both the duration of SMAD2/3 phosphorylation and nuclear accumulation. E-box motifs (CACGTG) in the PE1/PE2 promoter regions of the human PAI-1 gene, moreover, are platforms for a MAP kinase-directed USF subtype switch (USF-1-->USF-2) in response to growth factor addition suggesting that the EGFR-->MEK/ERK axis impacts PAI-1 expression, at least partly, through USF-dependent transcriptional controls. This paper reviews recent data suggesting the essential cooperativity among the EGFR-->MAP kinase cascade, the Rho/ROCK pathway and SMADs in TGF-beta1-initiated PAI-1 expression. The continued clarification of mechanistic controls on PAI-1 transcription may lead to new targeted therapies and clinically-relevant options for the treatment of vascular diseases in which PAI-1 dysregulation is a major underlying pathogenic feature.