Pathogenesis Of Vascular Disease Research Articles

Healthy plasma lipidomic signatures depend on sex, age, body mass index, and contraceptives but not perceived stress.

Perceived stress is thought to contribute to the pathogenesis of metabolic, vascular, mental, and immune diseases, with different susceptibilities in women and men. The present study investigated if and how perceived stress and/or demographic variables including sex, age, body mass index, regular prescription drugs, occasional analgesics, or dietary supplements manifested in plasma lipidomic profiles, obtained by targeted and untargeted mass spectrometry analyses. The study included 217 healthy women and 108 healthy men, aged 18-68 years, who were recruited in a 2:1 female:male ratio to account for women with/without contraceptives. As expected, dehydroepiandrosterone sulfate (DHEAS) and ceramides were higher in men than women, and DHEAS decreased with age, while ceramides increased. Contrary to expectations, neither DHEAS nor ceramides were associated with perceived stress (PSQ30 questionnaire), which was however, associated with BMI in men, but not in women. None of the lipid species or classes showed a similar "age X sex X BMI" interaction, but the endocannabinoid palmitoylethanolamide (PEA) correlated with BMI and hypertension. Independent of perceived stress, lysophosphatidylcholines (LPCs) were lower in women than men, whereas LPC metabolites, lysophosphatidic acids (LPAs), were higher in women. The LPA:LPC ratio was particularly high in women using oral contraceptives suggesting a strong hormone-induced extracellular conversion of LPCs to LPAs, which is catalyzed by the phospholipase D, autotaxin. The results reveal complex sex differences in perceived stress and lipidomic profiles, the latter being exacerbated by contraceptive use, but perceived stress and lipids were not directly correlated.

Hsa_circ_0007765 Promotes Platelet-Derived Growth Factor-BB-Induced Proliferation and Migration of Human Aortic Vascular Smooth Muscle Cells in Atherosclerosis.

Humanaorticvascularsmoothmusclecells (HA-VSMCs) play vital roles in the pathogenesis ofvasculardiseases, including Atherosclerosis (AS). Circular RNAs (circRNAs) have been reported to regulate the biological functions of HA-VSMCs.Therefore, this study aimed to explore the role and mechanism of hsa_circRNA_102353 (circ_0007765) in platelet-derived growth factor-BB (PDGF-BB)-induced HA-VSMCs. Circ_0007765, microRNA-654-3p (miR-654-3p), and Fibroblast Growth Factor Receptor Substrate 2 (FRS2) expression were measured using real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferative ability, invasion, and migration were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), Transwell, and wound healing assays. CyclinD1, MMP2, and FRS2 protein levels were assessed using a Western blot assay. Binding between miR-654-3p and circ_0007765 or FRS2 was predicted by Circinteractome or TargetScan, and verified using dual-luciferase reporter and RNA pull-down assays. PDGF-BB induced HA-VSMC proliferation, invasion, and migration. Circ_0007765 and FRS2 expression levels were increased in PDGF-BB-treated HA-VSMCs, and the miR-654-3p level was reduced. Moreover, circ_0007765 absence hindered PDGF-BB-induced HA-VSMC proliferation, invasion, and migration in vitro. At the molecular level, circ_0007765 increased FRS2 expression by acting as a sponge for miR-654-3p. Our findings revealed that circ_0007765 boosted PDGF-BB-induced HA-VSMC proliferation and migration through elevating FRS2 expression via adsorbing miR-654-3p, providing a feasible therapeutic strategy for AS.

Neuroimmune modulation for targeting organ damage in hypertension and atherosclerosis.

The brain is essential for processing and integrating sensory signals coming from peripheral tissues. Conversely, the autonomic nervous system regulated by brain centres modulates the immune responses involved in the genesis and progression of cardiovascular diseases. Understanding the pathophysiological bases of this relationship established between the brain and immune system is relevant for advancing therapies. An additional mechanism involved in the regulation of cardiovascular function is provided by the brain-mediated control of the renin-angiotensin system. In both cases, the communication is typically bidirectional and established by afferent and sensory signals collected at the level of peripheral tissues, efferent circuits, as well as of hormones. Understanding how the brain mediates the bidirectional communication and how the immune system participates in this process is object of intense investigation. This review examines key findings that support a role for these interactions in the pathogenesis of major vascular diseases that are characterized by a consistent alteration of the immune response, such as hypertension and atherosclerosis. In addition, we provide a critical appraisal of the translational implications that these discoveries have in the clinical setting where an effective management of neuroimmune and/or neuroinflammatory state might be beneficial.

Changes of the peripapillary vascular parameters in premature infants without retinopathy of prematurity using U-net segmentation.

To quantitatively assess the changes in mean vascular tortuosity (mVT) and mean vascular width (mVW) around the optic disc and their correlation with gestational age (GA) and birth weight (BW) in premature infants without retinopathy of prematurity (ROP). A single-center retrospective study included a total of 133 (133 eyes) premature infants [mean corrected gestational age (CGA) 43.6wk] without ROP as the premature group and 130 (130 eyes) CGA-matched full-term infants as the control group. The peripapillary mVT and mVW were quantitatively measured using computer-assisted techniques. Premature infants had significantly higher mVT (P=0.0032) and lower mVW (P=0.0086) by 2.68 (104 cm-3) and 1.85 µm, respectively. Subgroup analysis with GA showed significant differences (P=0.0244) in mVT between the early preterm and middle to late preterm groups, but the differences between mVW were not significant (P=0.6652). The results of the multiple linear regression model showed a significant negative correlation between GA and BW with mVT after adjusting sex and CGA (P=0.0211 and P=0.0006, respectively). For each day increase in GA at birth, mVT decreased by 0.1281 (104 cm-3) and for each 1 g increase in BW, mVT decreased by 0.006 (104 cm-3). However, GA (P=0.9402) and BW (P=0.7275) were not significantly correlated with mVW. Preterm birth significantly affects the peripapillary vascular parameters that indicate higher mVT and narrower mVW in premature infants without ROP. Alterations in these parameters may provide new insights into the pathogenesis of ocular vascular disease.

Perivascular Adipose Tissue and Perivascular Adipose Tissue-Derived Extracellular Vesicles: New Insights in Vascular Disease.

Perivascular adipose tissue (PVAT) is a special deposit of fat tissue surrounding the vasculature. Previous studies suggest that PVAT modulates the vasculature function in physiological conditions and is implicated in the pathogenesis of vascular diseases. Understanding how PVAT influences vasculature function and vascular disease progression is important. Extracellular vesicles (EVs) are novel mediators of intercellular communication. EVs encapsulate molecular cargo such as proteins, lipids, and nucleic acids. EVs can influence cellular functions by transferring the carried bioactive molecules. Emerging evidence indicates that PVAT-derived EVs play an important role in vascular functions under health and disease conditions. This review will focus on the roles of PVAT and PVAT-EVs in obesity, diabetic, and metabolic syndrome-related vascular diseases, offering novel insights into therapeutic targets for vascular diseases.

Exploring the pathogenesis of pulmonary vascular disease.

Pulmonary hypertension (PH) is a complex cardiopulmonary disorder impacting the lung vasculature, resulting in increased pulmonary vascular resistance that leads to right ventricular dysfunction. Pulmonary hypertension comprises of 5 groups (PH group 1 to 5) where group 1 pulmonary arterial hypertension (PAH), results from alterations that directly affect the pulmonary arteries. Although PAH has a complex pathophysiology that is not completely understood, it is known to be a multifactorial disease that results from a combination of genetic, epigenetic and environmental factors, leading to a varied range of symptoms in PAH patients. PAH does not have a cure, its incidence and prevalence continue to increase every year, resulting in higher morbidity and mortality rates. In this review, we discuss the different pathologic mechanisms with a focus on epigenetic modifications and their roles in the development and progression of PAH. These modifications include DNA methylation, histone modifications, and microRNA dysregulation. Understanding these epigenetic modifications will improve our understanding of PAH and unveil novel therapeutic targets, thus steering research toward innovative treatment strategies.

Correlation Between Elevated Lipoprotein(a) and Carotid Plaque in Asymptomatic Individuals

Background: Carotid plaque formation is a major global health issue and contributes in pathogenesis of vascular diseases. Lipoprotein(a), similar to low-density lipoprotein, may influence atherogenesis by promoting inflammation and thrombosis. However, the association between lipoprotein(a) levels and presence of carotid plaques has been debated. This study investigated the correlation between these parameters.Methods: We retrospectively analyzed 4,896 individuals who underwent lipoprotein(a) measurement and carotid ultrasonography at Gangnam Severance Hospital between January 2017 and December 2022. The relationship between lipoprotein(a) levels and the presence of carotid plaques was evaluated using logistic regression analysis adjusted for factors such as age, sex, hypertension (HTN), dyslipidemia, and diabetes mellitus (DM).Results: Among the 4,896 enrolled participants, those with carotid plaques were older, more likely to be men, and had a higher prevalence of HTN, DM, and dyslipidemia. The analysis showed a significant association between the presence of carotid plaques and a level of lipoprotein(a) ≥50 mg/dL in both univariable (unadjusted odds ratio=1.508, <i>p</i><0.001, 95% confidence interval: 1.192–1.907) and multivariable (adjusted odds ratio=1.335, <i>p</i>=0.029, 95% confidence interval: 1.030–1.731) models.Conclusion: Elevated lipoprotein(a) level emerged as an independent risk factor for carotid plaque formation, emphasizing the need for integrated risk assessment. Targeting lipoprotein(a) could enhance preventive strategies against cerebrovascular events. Therefore, further research is warranted to elucidate this disease’s underlying mechanisms and evaluate therapeutic interventions.

Regulated vascular smooth muscle cell death in vascular diseases.

Regulated cell death (RCD) is a complex process that involves several cell types and plays a crucial role in vascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant elements of the medial layer of blood vessels, and their regulated death contributes to the pathogenesis of vascular diseases. The types of regulated VSMC death include apoptosis, necroptosis, pyroptosis, ferroptosis, parthanatos, and autophagy-dependent cell death (ADCD). In this review, we summarize the current evidence of regulated VSMC death pathways in major vascular diseases, such as atherosclerosis, vascular calcification, aortic aneurysm and dissection, hypertension, pulmonary arterial hypertension, neointimal hyperplasia, and inherited vascular diseases. All forms of RCD constitute a single, coordinated cell death system in which one pathway can compensate for another during disease progression. Pharmacologically targeting RCD pathways has potential for slowing and reversing disease progression, but challenges remain. A better understanding of the role of regulated VSMC death in vascular diseases and the underlying mechanisms may lead to novel pharmacological developments and help clinicians address the residual cardiovascular risk in patients with cardiovascular diseases.

BMP9 attenuates IL-33 signaling and prevents endothelial-to-mesenchymal transition in pulmonary arterial hypertension

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Cardiovascular Alliance - PHAEDRA IMPACT Background Pulmonary Arterial hypertension (PAH) is a rare and progressive disease characterized by increased vascular resistance and remodeling of the pulmonary arteries. Disturbed Transforming growth factor (TGF)-β signaling, often associated with mutations in the gene encoding for the bone morphogenic protein receptor type II (BMPR2) and endothelial-to-mesenchymal transition (EndMT), emerges as a central culprit in the pathogenesis of PAH. Interleukin-33 (IL-33) has been identified as an inducer of EndMT, and its soluble receptor ST2 (sST2) has emerged as a potential biomarker for PAH. Bone morphogenic protein (BMP) 9, a BMPR2 ligand, showing a high affinity for endothelial cells, is being explored as a therapeutic approach. Purpose We hypothesize that a crosstalk between the TGF-β pathway and IL-33, a known promoter of vascular remodeling, occurs in PAH. This study aims to unravel the protective role of BMP9 in PAH, with a specific focus on the involvement of EndMT, a key player in the pathogenesis of vascular diseases. Methods The expression of IL-33 protein levels was assessed in Pulmonary Arterial Endothelial Cells (PAEC) and in lung tissues from experimentally induced PH (Sugen/Hypoxia (SuHx)) or control mice. Signal transduction and EndMT were investigated in PAECs exposed to IL-33, BMP9 and sST2, by gene expression analysis (qPCR), western blotting, ELISA and immunostaining. BMP9 and sST2 levels were measured in plasma from PAH patients by ELISA. Results Elevated IL-33 expression was observed in PAEC from PAH patients and lung tissues from SuHx mice compared to healthy controls. In vitro, BMP9 significantly induced the expression of the IL-33 soluble receptor ST2, while concurrently reducing IL-33 target gene expression. IL-33-induced EndoMT in PAEC was effectively mitigated by pre-incubation with BMP9, proving more efficacious than ST2 neutralizing antibody. Furthermore, a correlation between BMP9 and sST2 levels in plasma from PAH patients was identified. Conclusion Our findings demonstrate that BMP9 offers superior protections against IL-33-induced EndMT in PAECs compared to a ST2 neutralizing antibody. BMP9 induces expression of sST2, leading to IL-33 neutralization and subsequent EndMT inhibition. Therefore, targeting the IL-33 pathway in PAH patients presents a promising therapeutic option for preventing EndMT. This study provides novel insights into the pathogenesis of PAH, revealing a potential therapeutic target for this rare disease.BMP9 inhibits IL-33 downstream signalingBMP9 protects from IL-33-induced EndMT

Abstract 1132: Cellular Senescence Impairs The Maturity Of Cell-cell Junction In Vascular Endothelial Cells

Background and hypothesis: Vascular endothelial cells functionally differentiate upon formation of secure cell-cell junction. Disruption of cell-cell junction causes endothelial dysfunction and contributes to the early phase of pathogenesis of vascular diseases. Cellular senescence loosens cell-cell junction and causes endothelial dysfunction. We reported that the “maturity” of cell-cell junction determines how endothelial cells respond to the proinflammatory and proapoptotic insults. We hypothesize that cellular senescence affects the maturity of cell-cell junction. Methods and Results: Thrombin (1 U/mL) decreased a trans-endothelial electrical resistance (TEER) and transiently increased di-phosphorylation of myosin light chain (ppMLC) at 3 min in culture porcine aortic endothelial cells (PAEC) of lower passages (9-15 passages) at confluence. Fluorescence staining revealed that thrombin induced actin bundle formation, which was associated with ppMLC, but not pMLC (mono-phosphorylation), at cell periphery as initial events, followed by reorganization into actin stress fibers associated with both pMLC and ppMLC as later events. In contrast, PAEC of lower passages either at early culture day (3 days) or at confluence but in the absence of extracellular Ca 2+ exhibited instantaneous appearance of actin stress fibers associated with pMLC and ppMLC upon thrombin stimulation. Initial appearance of peripheral actin bundles in response to thrombin is one of the hallmarks of the mature cell-cell junction. When replicative senescence was induced by repeated passages (23-30 passages), senescent PAEC exhibited scattered actin stress fibers without any stimulation, and substantially increased actin stress fibers, with no peripheral actin bundles, after thrombin stimulation. Cellular senescence was confirmed by an increase in senescence-associated β-galactosidase activity. As a functional consequence, senescent PAEC exhibited augmented store-operated Ca 2+ entry induced by an inhibitor of endoplasmic Ca 2+ ATPase. Conclusions: Replicative cellular senescence impairs the maturity of cell-cell junction, thereby damaging the junctional integrity and physiological function of endothelial cells.

The role of transcription factors in the pathogenesis and therapeutic targeting of vascular diseases.

Transcription factors (TFs) constitute an essential component of epigenetic regulation. They contribute to the progression of vascular diseases by regulating epigenetic gene expression in several vascular diseases. Recently, numerous regulatory mechanisms related to vascular pathology, ranging from general TFs that are continuously activated to histiocyte-specific TFs that are activated under specific circumstances, have been studied. TFs participate in the progression of vascular-related diseases by epigenetically regulating vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). The Krüppel-like family (KLF) TF family is widely recognized as the foremost regulator of vascular diseases. KLF11 prevents aneurysm progression by inhibiting the apoptosis of VSMCs and enhancing their contractile function. The presence of KLF4, another crucial member, suppresses the progression of atherosclerosis (AS) and pulmonary hypertension by attenuating the formation of VSMCs-derived foam cells, ameliorating endothelial dysfunction, and inducing vasodilatory effects. However, the mechanism underlying the regulation of the progression of vascular-related diseases by TFs has remained elusive. The present study categorized the TFs involved in vascular diseases and their regulatory mechanisms to shed light on the potential pathogenesis of vascular diseases, and provide novel insights into their diagnosis and treatment.

RNF213-Related Vasculopathy: Various Systemic Vascular Diseases Involving RNF213 Gene Mutations: Review.

Moyamoya disease (MMD) is a cerebrovascular disorder that is predominantly observed in women of East Asian descent, and is characterized by progressive stenosis of the internal carotid artery, beginning in early childhood, and a distinctive network of collateral vessels known as "moyamoya vessels" in the basal ganglia. Additionally, a prevalent genetic variant found in most MMD cases is the p.R4810K polymorphism of RNF213 on chromosome 17q25.3. Recent studies have revealed that RNF213 mutations are associated not only with MMD, but also with other systemic vascular disorders, including intracranial atherosclerosis and systemic vascular abnormalities such as pulmonary artery stenosis and coronary artery diseases. Therefore, the concept of "RNF213-related vasculopathy" has been proposed. This review focuses on polymorphisms in the RNF213 gene and describes a wide range of clinical and genetic phenotypes associated with RNF213-related vasculopathy. The RNF213 gene has been suggested to play an important role in the pathogenesis of vascular diseases and developing new therapies. Therefore, further research and knowledge sharing through collaboration between clinicians and researchers are required.

Vascular endothelial dysfunction induced by 3-bromofluoranthene via MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation

3-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in the fine particulate matter of air pollutants. Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular and vascular diseases. Little is known about the molecular mechanism of 3-BrFlu on endothelial dysfunction in vivo and in vitro assay. In the present study, 3-BrFlu included concentration-dependent changes in ectopic angiogenesis of the sub-intestinal vein and dilation of the dorsal aorta in zebrafish. Disruption of vascular endothelial integrity and up-regulation of vascular endothelial permeability were also induced by 3-BrFlu in a concentration-dependent manner through pro-inflammatory responses in vascular endothelial cells, namely, SVEC4-10 cells. Generation of pro-inflammatory mediator PGE2 was induced by 3-BrFlu through COX2 expression. Expression of COX2 and generation of pro-inflammatory cytokines, including TNFα and IL-6, were induced by 3-BrFlu through phosphorylation of NF-κB p65, which was mediated by phosphorylation of MAPK, including p38 MAPK, ERK and JNK. Furthermore, generation of intracellular ROS was induced by 3-BrFlu, which is associated with the down-regulated activities of the antioxidant enzyme (AOE), including SOD and catalase. We also found that 3-BrFlu up-regulated expression of the AOE and HO-1 induced by 3-BrFlu through Nrf-2 expression. However, the 3-BrFlu-induced upregulation of AOE and HO-1 expression could not be revised the responses of vascular endothelial dysfunction. In conclusion, 3-BrFlu is a hazardous substance that results in vascular endothelial dysfunction through the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.

Kidney Renin-Angiotensin System: Lost in a RAS Cascade.

Renin was discovered more than a century ago. Since then, the functions of the renin-angiotensin system in the kidney have been the focus of intensive research revealing its importance in regulation of renal physiology and in the pathogenesis of heart, vascular, and kidney diseases. Inhibitors of renin-angiotensin system components are now foundational therapies for a range of kidney and cardiovascular diseases from hypertension to heart failure to diabetic nephropathy. Despite years of voluminous research, emerging studies continue to reveal new complexities of the regulation of the renin-angiotensin system within the kidney and identification of nonclassical components of the system like the prorenin receptor (PRR) and ACE2 (angiotensin-converting enzyme 2), with powerful renal effects that ultimately impact the broader cardiovascular system. With the emergence of a range of novel therapies for cardiovascular and kidney diseases, the importance of a detailed understanding of the renin-angiotensin system in the kidney will allow for the development of informed complementary approaches for combinations of treatments that will optimally promote health and longevity over the century ahead.

The angiotensin II type 1 receptor mediates the induction of oxidative stress, apoptosis, and autophagy in HUVECs induced by angiotensin II

Angiotensin (Ang) II, which is the central effector of the renin-angiotensin system (RAS), is one of the principal mediators of vascular dysfunction in hypertension and cardiovascular diseases. Proper vascular function is mediated by oxidative stress, cell apoptosis, and autophagy. However, the underlying signaling pathways and the major RAS components involved in this process are still not fully understood. In the present study, the effect of Ang II on reactive oxygen species (ROS) production, apoptosis induction, and autophagy in human umbilical vein endothelial cells (HUVECs) was investigated. An Annexin V kit was used for the apoptosis analysis, and caspase-3/7 activities were measured with the Caspase-Glo 3/7 Assay Kit. ROS production was measured using a 2,7-dichlorodihydrofluorescein diacetate probe whereas detection of autophagy was performed using acridine orange staining. We found that Ang II increases oxidative stress via ROS production, cell apoptosis via caspase 3/7, and the mitochondrial membrane potential (MMP). Interestingly, losartan, being an antagonist of the angiotensin II type 1 receptor (AT1R), has demonstrated the ability to restore autophagy levels to that of the control group subsequent to its induction by Ang II. The latter can thus induce endothelial cell damage, through excessive oxidative stress and defective autophagy-related apoptosis, which can be inhibited by losartan. These findings reinforce the pivotal role played by the Ang II/AT1R axis in the pathogenesis of vascular damage and bolster our knowledge of the role played by ROS/autophagy-related apoptosis via AT1R in the pathogenesis of hypertension and vascular diseases.

Phenotypic switching of vascular smooth muscle cells in atherosclerosis, hypertension, and aortic dissection.

Vascular smooth muscle cells (VSMCs) play a critical role in regulating vasotone, and their phenotypic plasticity is a key contributor to the pathogenesis of various vascular diseases. Two main VSMC phenotypes have been well described: contractile and synthetic. Contractile VSMCs are typically found in the tunica media of the vessel wall, and are responsible for regulating vascular tone and diameter. Synthetic VSMCs, on the other hand, are typically found in the tunica intima and adventitia, and are involved in vascular repair and remodeling. Switching between contractile and synthetic phenotypes occurs in response to various insults and stimuli, such as injury or inflammation, and this allows VSMCs to adapt to changing environmental cues and regulate vascular tone, growth, and repair. Furthermore, VSMCs can also switch to osteoblast-like and chondrocyte-like cell phenotypes, which may contribute to vascular calcification and other pathological processes like the formation of atherosclerotic plaques. This provides discusses the mechanisms that regulate VSMC phenotypic switching and its role in the development of vascular diseases. A better understanding of these processes is essential for the development of effective diagnostic and therapeutic strategies.

Small-molecule agonist AdipoRon alleviates diabetic retinopathy through the AdipoR1/AMPK/EGR4 pathway.

Diabetes mellitus (DM) is a progressive disease that involves multiple organs due to increased blood glucose, and diabetic retinopathy (DR) is the main complication of DM in the eyes and causes irreversible vision loss. In the pathogenesis of diabetic vascular disease, oxidative stress caused by hyperglycemia plays an important role in Müller cell impairment. In recent years, AdipoRon, an adiponectin analog that demonstrated important physiological functions in obesity, diabetes, inflammation, and cardiovascular diseases, demonstrated cellular protection from apoptosis and reduced inflammatory damage through a receptor-dependent mechanism. Here, we investigated how AdipoRon reduced oxidative stress and apoptosis in Müller glia in a high glucose environment. By binding to adiponectin receptor 1 on Müller glia, AdipoRon activated 5' adenosine monophosphate-activated protein kinase (AMPK)/acetyl-CoA carboxylase phosphorylation downstream, thereby alleviating oxidative stress and eventual apoptosis of cells and tissues. Transcriptome sequencing revealed that AdipoRon promoted the synthesis and expression of early growth response factor 4 (EGR4) and inhibited the cellular protective effects of AdipoRon in a high-glucose environment by reducing the expression of EGR4. This indicated that AdipoRon played a protective role through the EGR4 and classical AMPK pathways. This provides a new target for the early treatment of DR.

Microvascular Shunts, Intracranial Pressure, and the Impact of Drag-Reducing Polymers.

In the 50 years of my membership in ISOTT, I, Edwin M Nemoto, have enjoyed the application of many of the technologies developed in our society including microelectrodes for pH, PO2, and near-infrared spectroscopy (NIRS) in the measurement of tissue oxygenation and metabolism. The greatest joy has been the number of great scientists I have had the pleasure of knowing and exchanging scientific ideas with across the United States, Europe, and Asia. This will be the enduring legacy of ISOTT for me personally as we continue beyond our half-century existence.Every organ in our body, including the tegmentum, is endowed with microvascular shunts (MVS), which may be involved in physiological regulation, i.e. temperature regulation or pathophysiological responses to tissue injury and oedema. MVS that open in response to increased capillary resistance and tissue oedema in the brain, heart, kidneys, liver, and muscles conduct neither nutrient nor gas exchange with tissue promoting tissue oedema in a vicious cycle. Pharmacologic arteriolar vasodilation cannot correct the MVS flow as may occur after a stroke or traumatic brain injury because pan arteriolar vasodilation would shunt flow to the normal tissue and away from the injured brain in a "reverse" steal or a "Robin Hood" phenomenon. A high molecular weight (4000kDa) drag-reducing polymer (DRP) of polyethylene oxide or Lamiflo™ enhances blood flow by altering the physical dynamics of red blood cells (RBC) and blood flow, increasing the shear rate in the microvasculature and capillaries where shear rate is highest as it is inversely proportional to the 3rd power of blood vessel diameter. The shear rate sensed on the endothelium through the glycocalyx exerts precise control of endothelial function, including endothelial water permeability, nitric oxide synthase activity, lymphocyte adhesion to and transport across the endothelium, and microglial activation, all in response to low endothelial shear rate. DRP has proven effective in reversing MVS flow and increasing capillary flow in haemorrhagic shock, myocardial ischaemia, stroke, renal ischaemia, traumatic brain injury, stroke, sepsis, and Alzheimer's Disease. Our aim is to establish the universality of MVS in the pathogenesis of vascular disease and in taking DRP to clinical treatment of vascular diseases.

The role of pericyte in ocular vascular diseases.

Pericytes are located in the stromal membrane of the capillary outer wall and contain endothelial cells (ECs). They are pivotal in regulating blood flow, enhancing vascular stability, and maintaining the integrity of the blood-retina barrier (BRB)/blood-brain barrier (BBB). The pluripotency of pericytes allows them to differentiate into various cell types, highlighting their significance in vascular disease pathogenesis, as demonstrated by previous studies. This potential enables pericytes to be a potential biomarker for the diagnosis and a target for treatment of vascular disorders. The retina, an essential part of the eyeball, is an extension of cerebral tissue with a transparent refractive medium. It offers a unique window for assessing systemic microvascular lesions. Routine fundus examination is necessary for patients with diabetes and hypertension. Manifestations, such as retinal artery tortuosity, dilation, stenosis, and abnormal arteriovenous anastomosis, serve as typical hallmarks of retinal vasculopathy. Therefore, studies of ocular vascular diseases significantly facilitate the exploration of systemic vascular diseases.

Surgical Significance of Variant Anatomy of Inferior Mesenteric Artery and Left Colic Artery: A Computed Tomography Angiographic Study

Introduction: A variation in vessel morphology determines flow dynamics and vascular disease pathogenesis. Definite information on the distinctive anatomical variations of the mesenteric vessels is extremely important for laparoscopic surgical procedures and interventional radiological procedures in the abdominal region. Three-dimensional-computed tomography angiography (3D-CTA) is a less invasive method to evaluate vascular anatomy using a visual tracking method on high-definition images, contrast-enhanced inferior mesenteric artery (IMA) can be traced to its terminal branches beside the colon wall. Subjects and Methods: Abdominal contrast-enhanced computed tomography scan data from 180 patients was retrospectively collected, reconstructed, and analyzed. The origin, length of IMA from origin to the first branch, branching patterns of IMA, and tracking patterns of the ascending branch of left colic artery (LCA), were examined, and their associations with clinical features were analyzed. Results: IMA displayed variations in the level of origin ranging from upper 1/3 of L3 to upper 1/3 of L4, mean length from origin to the first branch was 27.4 ± 7.8 mm. Observed branching patterns of IMA were grouped according to Yada classification: Type 1 (52.2%), Type 2 (15.5%), Type 3 (14.4%), and Type 4 (17.7%). Tracking of the ascending branch of LCA before anastomosis with marginal artery revealed four patterns: Type A LCA pattern in 43.9%; Type B LCA anatomy pattern was (19.4%); Type C LCA anatomy pattern was (20.0%); and Type D LCA anatomy pattern was observed (16.7%). Conclusion: Preoperative understanding of the vascular variations of IMA and LCA can be obtained by 3D-CTA. This may be helpful to surgeons in planning preoperative strategies to prevent iatrogenic injuries.