Arteriolar Vessels Research Articles

Skeletal stem and progenitor cells in bone physiology, ageing and disease.

Skeletal stem cells (SSCs) and related progenitors with osteogenic potential, collectively termed skeletal stem and/or progenitor cells (SSPCs), are crucial for providing osteoblasts for bone formation during homeostatic tissue turnover and fracturerepair. Besides mediating normal bone physiology, they also have important roles in various metabolic bone diseases, including osteoporosis. SSPCs are of tremendous interest because they represent prime future targets for osteoanabolic therapies and bone regenerative medicine. Remarkable progress has been made in characterizing various SSC and SSPC populations in postnatal bone. SSPCs exist in the periosteum and within the bone marrow stroma, including subsets localizing around arteriolar and sinusoidal blood vessels; they can display osteogenic, chondrogenic, adipogenic and/or fibroblastic potential, and exert critical haematopoiesis-supportive functions. However, much remains to be clarified. By the current markers, bona fide SSCs are commonly contained within broader SSPC populations characterized by considerable heterogeneity and overlap, whose common versus specific functions in health and disease have not been fully unravelled. Here, we review the present knowledge of the identity, fates and relationships of SSPC populations in the postnatal bone environment, their contributions to bone maintenance, the changes observed upon ageing, and the effect of metabolic diseases such as osteoporosis and diabetes mellitus.

Association of retinal microvascular curve tortuosity and multiple sclerosis: A cross-section analysis from the UK Biobank

BackgroundThere is growing evidence supporting that vascular abnormalities contribute to multiple sclerosis (MS), and retinal microvasculature functions as a visible window to observe vessels. We hypothesized that retinal vascular curve tortuosity is associated with MS, which this study aims to address. MethodsParticipants from the UK Biobank with complete clinical records and gradable fundus photos were included in the study. Arteriolar and venular curve tortuosity and vessel area density are quantified automatically using a deep learning system. Individuals with MS were matched to healthy controls using propensity score matching (PSM). Conditional logistic regression was used to investigate the association between retinal vascular characteristics and MS. We also used a receiver operating characteristic (ROC) curve to assess the diagnostic performance of MS. ResultsVenular curve tortuosity (VCT) was found to be significantly associated with MS. And patients with multiple sclerosis were probable to have lower VCT than the non-MS group (OR = 0.22 [95 % CI, 0.05 to 0.92], P < 0.05). ConclusionsOur study reveals a significant association between vessel curve tortuosity and MS. The lower curve tortuosity of the retinal venular network may indicate a higher risk of incident multiple sclerosis.

Evaluation of renal resistive index and new biomarkers in post-hepatitis C cirrhosis patients for developing kidney injury

Background In liver cirrhosis, hemodynamic changes in splanchnic and systemic circulations are involved. Indeed, no established laboratory markers for altered renal hemodynamics in cirrhosis were implicated. The duplex Doppler waveform analysis of intrarenal arteriolar vessels is considered a noninvasive estimate of renovascular impedance and renal arterial vasoconstriction. In particular, the renal resistive index (RRI) is considered as the best reliable indicator of renal blood flow in patients with different diseases. The study aimed to evaluate RRI, serum and urinary cystatin C, beta-trace protein, liver fatty acid protein, and kidney injury molecule-I as noninvasive indicators of altered renal hemodynamics in patients with cirrhosis with normal urea and creatinine. Patients and methods A case–control study included 60 patients with post-hepatitis C virus (HCV) cirrhosis and 40 healthy controls. Serum and urinary biomarkers were measured. Renal color Doppler duplex was used to evaluate RRI. Results Mean serum and urinary biomarkers in HCV patients were significantly higher than controls. Moreover, the RRI was higher in patients than in controls with P value less than 0.001. Rising levels of urea, high direct bilirubin, and hypoprothrombinemia with high serum kidney injury molecule 1 and RRI were significant independent predictors for subsequent kidney injury. Conclusion Urinary kidney injury molecule 1 is a reliable, sensitive, and specific biomarker for the prediction of kidney injury among HCV cirrhotic patients with an obvious superior test performance and specificity to e other biomarkers. An increase in serum kidney injury molecule 1 and RRI were associated with poor prognosis.

Endothelial dysfunction in retinal vessels of hemodialysis patients compared to healthy controls

Endothelial dysfunction is a key factor promoting atherosclerosis and cardiovascular complications. Hemodialysis patients typically show various cardiovascular complications and impaired retinal venular dilation has been described as a risk factor for mortality. Non-invasive retinal vessel analysis provides insight into the microvasculature and endothelial function. Static retinal vessel analysis determines arteriolar and venular vessel diameters and dynamic retinal vessel analysis measures microvascular function by flicker-light induced stimulation, which results in physiological dilation of retinal vessels. We measured 220 healthy individuals and compared them to our preexisting cohort of hemodialysis patients (275 for static and 214 for dynamic analysis). Regarding static vessel diameters, hemodialysis patients and healthy individuals did not significantly differ between vessel diameters. Dynamic retinal vessel analysis showed attenuated dilation of the arteriole of hemodialysis patients with 1.6% vs 2.3% in healthy individuals (p = 0.009). Case–control matching for age (mean 65.4 years) did not relevantly diminish the difference. Hemodialysis patients also exhibited reduced venular dilation after matching for age (3.2% vs 3.8%, p = 0.019). Hemodialysis patients showed microvascular dysfunction compared to healthy individuals when using dynamic retinal vessel analysis. Further studies should focus on dynamic retinal vessel analysis which can add insights into the microvascular function and risk factors in multimorbid patients.

The vascular geometry of the choriocapillaris is associated with spatially heterogeneous molecular exchange with the outer retina.

Vision relies on the continuous exchange of material between the photoreceptors, retinal pigment epithelium and choriocapillaris, a dense microvascular bed located underneath the outer retina. The anatomy and physiology of the choriocapillaris and their association with retinal homeostasis have proven difficult to characterize, mainly because of the unusual geometry of this vascular bed. By analysing tissue dissected from 81 human eyes, we show that the thickness of the choriocapillaris does not vary significantly over large portions of the macula or with age. Assessments of spatial variations in the anatomy of the choriocapillaris in three additional human eyes indicate that the location of arteriolar and venular vessels connected to the plane of the choriocapillaris is non-random, and that venular insertions cluster around arteriolar ones. Mathematical models built upon these anatomical analyses reveal that the choriocapillaris contains regions where the transport of passive elements is dominated by diffusion, and that these diffusion-limited regions represent areas of reduced exchange with the outer retina. The width of diffusion-limited regions is determined by arterial flow rate and the relative arrangement of arteriolar and venular insertions. These analyses demonstrate that the apparent complexity of the choriocapillaris conceals a fine balance between several anatomical and functional parameters to effectively support homeostasis of the outer retina. KEY POINTS: The choriocapillaris is the capillary bed supporting the metabolism of photoreceptors and retinal pigment epithelium, two critical components of the visual system located in the outer part of the retina. The choriocapillaris has evolved a planar multipolar vascular geometry that differs markedly from the branched topology of most vasculatures in the human body. Here, we report that this planar multipolar vascular geometry is associated with spatially heterogenous molecular exchange between choriocapillaris and outer retina. Our data and analyses highlight a necessary balance between choriocapillaris anatomical and functional parameters to effectively support homeostasis of the outer retina.

Vascular Cell Adhesion Molecule-1 Regulates Bone Marrow Mesenchymal Stem Cell Maintenance and Niche Function

Bone marrow (BM) mesenchymal stem cells (MSCs) are rare non-hematopoietic perivascular stromal cells characterized by their unique ability to self-renew and differentiate into bone, cartilage, and fat, ensuring proper skeletal development and maintenance. Different subsets of BM MSCs associate with arteriolar and sinusoidal vessels to form specialized niches that regulate hematopoietic stem cell (HSC) function by secreting high levels of niche factors such as CXC-chemokine ligand 12 (CXCL12), stem cell factor (SCF), and Vascular Cell Adhesion Molecule-1 (VCAM1). VCAM1 is classically expressed on endothelial and stromal cells where it acts as an adhesion molecule that preferentially binds to α4β1 integrin on HSCs and progenitor cells (HSPCs). Deletion of Vcam1 in endothelial and hematopoietic cells induces HSPC mobilization into the peripheral blood without affecting endothelial cells homeostasis. Recent work from our lab further demonstrated that VCAM1 expression on HSCs and leukemic stem cells confers innate immune tolerance ( Nat Cell Biol 2022). While the contribution of HSC and endothelial-derived VCAM1 to homeostasis has been well studied, the role of MSC-derived VCAM1 on HSC and MSC maintenance and multilineage potency remains unknown. Our supporting data suggest that MSCs are the BM's main source of Vcam1 (p&amp;lt;0.0001) and that VCAM1 is critical for the maintenance, survival, and function of MSCs. Using a mouse model in which Vcam1 can be conditionally deleted in BM MSCs by a tamoxifen-inducible N-Cadherin-Cre ER line (referred to as Vcam1 N-CadCreER), we found that deletion of Vcam1 significantly reduces the number (4-fold, p=0.0030), frequency (4-fold, p=0.0042), and viability (2-fold, p=0.0039) of BM MSCs. Previous findings in breast cancer revealed that VCAM1 promotes PI3K/Akt survival signaling via Akt phosphorylation. Accordingly, Vcam1 deletion in N-Cadherin-Cre ER MSCs, demonstrated a significant reduction in phospho-Akt (Ser473) (p&amp;lt;0.05), supporting the role of VCAM1 in mediating PI3K/Akt survival signaling in MSCs. Intriguingly, the remaining viable VCAM1-null MSCs isolated from Vcam1 N-CadCreER mice exhibited reduced clonogenic potential (determined by CFU-F assays; 3-fold, p=0.0001). Furthermore, micro-CT analysis of 6-month-old Vcam1 N-CadCreER mice presented an altered bone phenotype compared to the control as evidenced by their significantly increased bone thickness and volume (p&amp;lt;0.05), yet significantly decreased tissue mineral density and medullary cavity area (p&amp;lt;0.05). Bulk RNA sequencing (RNAseq) of sorted viable MSCs revealed distinct grouping between Control and Vcam1 N-CadCreER MSCs. Gene ontology analysis demonstrated that deletion of Vcam1 caused an upregulation of pathways associated with inflammation and cytokine release while pathways associated with ossification, extracellular matrix organization, and skeletal development were all downregulated. Surprisingly, both bulk RNAseq and qPCR analysis confirmed a significant reduction in the expression of HSC niche factors ( Vcam1 Cxcl12 and Scf) following Vcam1 deletion, indicative of reduced niche activity. As expected, Vcam1 deletion in N-Cadherin-Cre ER MSCs, caused significant mobilization of HSCs into the blood (p&amp;lt;0.0001) and BM homing defects (p&amp;lt;0.05), however the number and repopulation capacity of BM HSCs remained unaltered, as seen by BM transplantation experiments. Surprisingly, imaging analysis of whole-mount bone marrow sternum of phenotypic HSCs revealed no differences in HSC niche localization between Vcam1-null and Control mice. Accordingly, ELISA analysis of BM extracellular fluid revealed no differences in overall CXCL12 and SCF levels suggesting that there may be some local or systemic niche compensation at play. Single-cell (sc)RNAseq of pooled BM and compact bone sorted non-hematopoietic stromal cells (DAPI -Lineage -CD45 -Ter119 -CD19 -CD71 -)from Vcam1 N-CadCreERand Control mice further confirmed the downregulation of HSC niche factors in MSCs, and overall remodeling of the BM stromal cell composition following Vcam1 deletion. Interestingly, our scRNAseq analysis revealed increased expression of Cxcl12 and Scf in specific vascular and stromal cell populations, supporting the notion of HSC niche compensation. Overall, these findings demonstrate that MSC-derived Vcam1 is critical for BM MSC survival and their HSC niche function.

RETINAL MICROVASCULAR CHANGES AND RISK OF CORONARY HEART DISEASE: A Systematic Review and Meta-Analysis.

To quantify associations between various retinal microvascular changes and the risk of the development of coronary heart disease (CHD). PubMed, Embase, Web of Science, and Cochrane Library databases were searched for cohort studies on the association between retinal microvascular changes and incident CHD up to July 31, 2023. The summary risk estimates were estimated using the random-effects model. Subgroup and sensitivity analyses were performed to investigate the potential source of heterogeneity. The authors identified 21 studies that met the inclusion criteria of this meta-analysis through database searching. This study yielded significant associations between retinal microvascular changes, including arteriolar narrowing, venular widening, vessel occlusion, and other retinal vascular signs, and the risk of CHD, with pooled adjusted hazard ratios of 1.20 (95% confidence interval: 1.13-1.27). In sex- and age-stratified analyses, retinal microvascular changes were associated with a greater risk of developing CHD in female patients and younger adults. A range of retinal microvascular changes was associated with the risk of CHD, particularly in female patients and younger ages. The results of this study support the concept that retinal microvascular abnormalities may be markers for future CHD. Noninvasive retinal microvascular assessments may be helpful in screening patients with increased CHD risk.

Retinal Vascular Geometry in Hypertension: cSLO-Based Method.

We aim to introduce a method using confocal scanning laser ophthalmoscopy (cSLO) images for measuring retinal vascular geometry, including vessel branch angle (BA), vessel diameter, vessel tortuosity, and fractal dimension (Df), and to elucidate the relationship between hypertension and these metrics. A total of 119 participants (119 eyes) were enrolled, among which 72 were normotensive and 47 were hypertensive. Infrared cSLO images were extracted from the circular scan around the optics disc using a commercial cSLO + optical coherence tomography instrument. Preprocessed cSLO images were further analyzed using the appropriate tool/macro/plugin of ImageJ. Intraclass correlation coefficients of selected methods used for conducting the cSLO-based geometric analyses were all higher than 0.80. Arterial/arteriolar BA, arteriolar vessel diameter, and total Df in normotensive subjects were 85.80 ± 7.79°, 116.80 ± 12.58μm, and 1.430 ± 0.037, respectively, significantly higher than those of hypertensive subjects (82.13 ± 10.83°, 108.2 ± 11.12μm, and 1.361 ± 0.044, all P < 0.05). The aforementioned metrics remained negatively correlated with hypertension even after adjusting for age alone or age and gender (P < 0.05). However, the difference between arteriolar tortuosity and all studied venous/venular geometric parameters in both subjects was insignificant (all P > 0.05). Proposed cSLO-based methods for assessing various vascular geometric parameters were highly repeatable and reproducible. Arterial/arteriolar BA, arteriolar vessel diameter, and total Df were retinal vascular parameters significantly correlated with hypertension in a negative manner.

Non-Invasive Metabolic and Structural Retinal Markers in Patients with Giant Cell Arteritis and Polymyalgia Rheumatica: A Cross-Sectional Study.

Giant cell arteritis (GCA) is a potential sight-threatening disease. Although it is associated with polymyalgia rheumatica (PMR), visual loss is not common in PMR. A retinal oximeter can be used to conduct a direct, non-invasive, in vivo assessment of the vascular system. In a cross-sectional study, we measured the retinal oxygen saturation and retinal vessel calibers in GCA patients, PMR patients, and control participants. Twenty GCA patients (38 eyes), 19 PMR patients (33 eyes), and 12 controls (20 eyes) were investigated. Images were analyzed using Oxymap Analyzer software 2.5.0 (Oxymap ehf., Reykjavik, Iceland). Groups were compared using an age- and sex-adjusted linear mixed model regression. The median (IQR) age for GCA patients was 69.0 (66.5–76.5) years, for PMR 69.0 (67.0–72.0) years, and for the controls 75.5 (71.5–81.0) years, respectively. As compared to the controls (115.3 µm), the retinal arterioles were significantly wider in patients with GCA (124.4 µm; p = 0.023) and PMR (124.8 µm; p = 0.049). No difference was found in the retinal venular caliber or vascular oxygen saturation. These results indicate that GCA and PMR patients differ similarly in the retinal arteriolar diameter compared to controls. Further studies are needed in order to clarify the underlying inflammatory mechanisms in retinal arteriolar vessels and if these parameters can be used to predict clinical outcomes.

Obesity, blood pressure and retinal microvascular phenotype in a bi-ethnic cohort of young children

Background and aimsChildhood obesity and high blood pressure (BP) are main determinants for cardiovascular disease development with regional and ethnic differences. Narrower arteriolar (CRAE) and wider venular (CRVE) retinal vessel diameters are sensitive markers of early vascular compromise in children. We aimed to compare retinal vessel diameters and investigate associations and odds ratios with body mass index (BMI) and BP in a multi-national/ethnic childhood study. MethodsBMI, systolic (SBP) and diastolic BP (DBP) were screened in 929 black and white South African (SA) and 1171 Swiss children (aged 5–9 years). Retinal assessments were performed using a retinal vessel analyzer to determine CRAE and CRVE. ResultsBlack SA children had wider CRVE compared to white SA and Swiss children (all p < 0.001). However, BMI or BP was not associated with CRVE in black SA children. Higher BMI and BP associated with narrower CRAE in all children, except for BMI in black SA children, in whom narrower CRAE was found for every unit increase in SBP (β = −0.199 μm, p = 0.001) and DBP (β = −0.312 μm, p < 0.001). Obesity (OR:1.38[1.01; 1.89]), hypertension (OR:1.90[1.53; 2.36]) and black ethnicity (OR:1.50[1.18; 1.92]) increased the likelihood for arteriolar narrowing. ConclusionsBlack SA children presented with wider retinal venules compared to their white SA and Swiss peers, which was unexplained by conventional risk factors. The overall risk of arteriolar narrowing was driven by obesity, hypertension and ethnicity. Our findings indicate the importance to differentiate cardiovascular risk by microvascular phenotype in different populations and ethnicity early in life.

Hepatic Hyaline Arteriolosclerosis in Patients with Chronic Hyperglycemia

Abstract Introduction/Objective Hyaline arteriolosclerosis is a common feature of diabetic microangiopathy. It results from hyperglycemia-induced endothelial cell dysfunction and can be found in many sites including the retina, kidney, and skin. This histologic finding is important because studies have shown that in the kidney it is an independent risk factor for cardiovascular complications. To our knowledge, an association between hyperglycemia and hyaline arteriolosclerosis in the liver has not be studied. We aimed to investigate whether chronic hyperglycemia is associated with this histologic finding in liver arterioles. Methods/Case Report The first 50 liver biopsies performed at our institution starting January 1, 2020 were scanned into a digital pathology system (Philips, Cambridge, MA). For each biopsy, the patient’s highest recorded hemoglobin A1c (HbA1c) up to one year from the date of biopsy was recorded. The biopsies were then grouped into two groups: those from patients with a HbA1c greater than 6.5%, and those with a HbA1c value less than 6.5 %. Next, the digested periodic acid Schiff (DPAS) intensity of the arteriolar vessels in each biopsy was graded 0 to 3 by a single pathology resident who was blinded to its corresponding HbA1c group. Grade 0 to 1 was considered negative staining. Grade 2 to 3 was considered positive staining and indicative of hyaline arteriolosclerosis. By the end of the data collection, each case had been given a staining category and a HbA1c group. A 2 x 2 contingency table was constructed. Results (if a Case Study enter NA) 37 of 50 patients had a recorded HbA1c meeting the study criteria. Of these 37 patients, 11 had an HbA1c greater than 6.5 % while 26 had an HbA1c less than 6.5%. Seven of the 11 biopsies from patients with an elevated HbA1c showed positive staining. Six of the 26 biopsies from patients with an HbA1c less than 6.5% showed positive staining. Conclusion We hypothesized that patients living with hyperglycemia may be more likely to exhibit hepatic hyaline arteriolosclerosis. A chi-squared test of independence was performed to examine the association between a liver biopsy’s HbA1c group and staining category. The relation between these variables was significant at p = &amp;lt; .05, χ 2 (2, N= 36) = 5.57, p = .0182, indicating liver biopsies with a HbA1c greater than 6.5 % are more likely to have this histologic finding. Future studies are needed to characterize diabetic hepatopathy, and its relatedness to macrovascular complications.

Thyroid Status and Brain Circulation: The Rotterdam Study.

ContextWhether thyroid dysfunction is related to altered brain circulation in the general population remains unknown.ObjectiveWe determined the association of thyroid hormones with different markers of brain circulation within community-dwelling elderly people.MethodsThis was a population-based study of 3 subcohorts of the Rotterdam Study, starting in 1989, 2000, and 2006. A total of 5142 participants (mean age, 63.8 years; 55.4% women), underwent venipuncture to measure serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4). Between 2005 and 2015, all participants underwent phase-contrast brain magnetic resonance imaging to assess global brain perfusion (mL of blood flow/100 mL of brain/minute). Arteriolar retinal calibers were assessed using digitized images of stereoscopic fundus color transparencies in 3105 participants as markers of microcirculation. We investigated associations of TSH, FT4 with brain circulation measures using (non)linear regression models.ResultsFT4 (in pmol/L) levels had an inverse U-shaped association with global brain perfusion, such that high and low levels of FT4 were associated with lower global brain perfusion than middle levels of FT4. The difference in global brain perfusion between high FT4 levels (25 pmol/L) and middle FT4 levels (FT4 = 15 pmol/L; P nonlinearity = .002) was up to –2.44 mL (95% CI –4.31; –0.56). Higher and lower levels of FT4, compared with middle FT4 levels, were associated with arteriolar retinal vessels (mean difference up to –2.46 µm, 95% CI –4.98; 0.05 for lower FT4).ConclusionThese results suggest that thyroid dysfunction could lead to brain diseases such as stroke or dementia through suboptimal brain circulation that is potentially modifiable.

Geometric Features of the Pial Arteriolar Networks in Spontaneous Hypertensive Rats: A Crucial Aspect Underlying the Blood Flow Regulation.

BackgroundSeveral studies indicate that hypertension causes major changes in the structure of the vessel wall by affecting the regulation of blood supply to the tissues. Recently, it has been observed that capillary blood flow is also considerably influenced by the structural arrangement of the microvascular networks that undergo rarefaction (reduction of the perfused vessel number). Therefore, this study aimed to assess the geometric arrangements of the pial arteriolar networks and the arteriolar rhythmic diameter changes in spontaneously hypertensive rats (SHRs).MethodsFluorescence microscopy was utilized to observe in vivo the pial microcirculation through a closed cranial window. Pial arterioles were classified according to Strahler’s method. The arteriolar rhythmic diameter changes were evaluated by a generalization short-time Fourier transform.ResultYoung SHRs showed four orders of vessels while the adult ones only three orders. The diameter, length, and branching number obeyed Horton’s law; therefore, the vessels were distributed in a fractal manner. Larger arterioles showed more asymmetrical branches than did the smaller ones in young SHRs, while in adult SHRs smaller vessels presented asymmetrical branchings. In adult SHRs, there was a significant reduction in the cross-sectional area compared with the young SHRs: this implies an increase in peripheral resistance. Young and adult age-matched normotensive rats did not show significant alterations in the geometric arteriolar arrangement with advancing age, both had four orders of arteriolar vessels, and the peripheral resistance did not change significantly. Conversely, the frequency components evaluated in arteriolar rhythmic diameter changes of young and adult SHRs showed significant differences because of a reduction in the frequency components related to endothelial activity detected in adult SHRs.ConclusionIn conclusion, hypertension progressively causes changes in the microarchitecture of the arteriolar networks with a smaller number of vessels and consequent reduced conductivity, characteristic of rarefaction. This was accompanied by a reduction in the formation and release of independent and dependent – endothelial nitric oxide components regulating arterial vasomotion.

Arteriolar Neovasculogenesis and Sinusoidal Collapse Are Pathologic Features of the Hematopoietic Stem Cell Niche in Sickle Cell Disease (SCD) Mice

Sickle cell disease is a worldwide distributed hereditary red cell disorder, caused by pathologic hemoglobin S (HbS). The main clinical manifestations of SCD are chronic hemolytic anemia and acute vaso-occlusion, leading to multiple end-organ complications. To what extent, vaso-occlusion may affect the bone marrow microenvironments that regulate hematopoiesis in SCD is poorly defined. Here, we first used quantitative 2-D and 3-D imaging analyses to study the bone marrow parenchyma. In 8-12 week-old SCD (SS) mice (humanized Townes model, SS), we observed a disorganized vasculature with both sinusoidal (laminin+ CD105+ Sca-1- alpha smooth muscle actin- ) and arteriolar (laminin+ CD105- Sca-1+ alpha smooth muscle actin+) structural abnormalities compared to healthy (AA) or HbS- carrier (SA) mice. The majority of sinusoids have either small or collapsed lumens, often filled with large Ter 119+ red blood cells (RBC) clumps, suggesting RBC sickling in localized areas. The RBC clumps involve significant numbers of Gr-1+/CD11b+ myeloid cells, which also are concentrated perisinusoidally consistent with a local inflammatory process. These features are amplified under hypoxia-reoxygenation conditions, used to mimick acute SCD vaso-occlusive crisis. Most strikingly, is the dramatic increase in small, tortuous artery/arteriole vessel formation, particularly in the central portions, i.e. non-endosteal regions, of the bone marrow cavity. Using laser scanning cytometry (LaSC) of whole femur sections, we determined a four fold increase in arterioles in the central bone marrow. In support of hypoxia induced pathways responsible for neovasculogenesis, we show that HIF-1alpha staining is dramatically increased in the bone marrow of SCD (SS) mice compared to healthy (AA) mice, and interestingly the distribution pattern also is concentrated to the central, non-endosteal portions of the marrow. Moreover the bone marrow supernatant, only in SS mice, exhibits high levels of vascular endothelial growth factor, VEGF in agreement with increased levels of HIF-1alpha. Because both the sinusoidal and arteriolar vascular structures are recognized components of the hematopoietic stem cell (HSC) niche, we explored the early stages of hematopoiesis by multiparameter flow cytometry. We found that the long term HSC population (Lin- Sca-1+ c-Kit+ CD48- CD150+) is reduced by 50% in SCD mice. Taken together, we propose a model for SCD bone marrow whereby vaso-occlusive events are accompanied by defects in both sinusoidal and arteriolar vessels and resultant severe tissue hypoxia. Finally, we speculate that the abnormal vascular niche structures in SS mice affect hematopoietic stem cell homeostasis, which requires further study. These findings may have significant implications for gene therapy protocols utilizing autologous hematopoietic stem cell transplantation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Fatal hemorrhage after tonsillectomy

AbstractThis is the first report of a segmental mediolysis occurring in arterioles, affecting the neck/tonsillar region and leading to a fatal hemorrhage after a tonsillectomy in a 20-year-old woman. Arteriolar mediolysis could be observed in tissue layers about 2 cm distant from the tonsillectomy region. Reparative changes were observed in the carotid and small neck arteries as well as in only one intramyocardial arteriole; however, no other vascular regions typically reported in segmental mediolysis arteriopathy were affected and aneurysm formation was not observed. No family history of vascular disease or hypertension was known. Pathophysiologically, previously reported reasons for post-tonsillectomy bleeding could be excluded. Segmental mediolysis may represent a wider spectrum of affected arteriolar vessels besides the reported small and medium sized arteries leading to aneurysms, which impedes radiographic diagnosis.

Optic Disc Features in Familial Retinal Arteriolar Tortuosity.

Describing optic disc appearance in familial retinal arteriolar tortuosity (fRAT) using multimodal imaging and raising awareness of peripapillary arterial changes due to this disorder. A cross-sectional study was performed in four consecutive patients of two non-related families. Detailed ophthalmological examination was performed and supported by medical and family history and multimodal imaging. In all subjects, increased tortuosity of second- and third-order retinal arteries in superior and deeper vascular plexus was documented. Furthermore, tortuosity in the peripapillary circle of Zinn-Haller was found. In addition, retinal vessel oximetry confirmed tortuosity only of the arterial vessels. The present data suggests that a blurry bordered, hyperemic optic disc in the presence of abnormally tortuous arteriolar vessels and asymptomatically or oligosymptomatically spontaneously resolved hemorrhages could be associated with a fRAT. This finding could be linked to peripapillary arterial vessel tortuosity.

High-salt intake affects retinal vascular tortuosity in healthy males: an exploratory randomized cross-over trial

The retinal microcirculation is increasingly receiving credit as a relatively easily accessible microcirculatory bed that correlates closely with clinical cardiovascular outcomes. The effect of high salt (NaCl) intake on the retinal microcirculation is currently unknown. Therefore, we performed an exploratory randomized cross-over dietary intervention study in 18 healthy males. All subjects adhered to a two-week high-salt diet and low-salt diet, in randomized order, after which fundus photographs were taken and assessed using a semi-automated computer-assisted program (SIVA, version 4.0). Outcome parameters involved retinal venular and arteriolar tortuosity, vessel diameter, branching angle and fractal dimension. At baseline, participants had a mean (SD) age of 29.8 (4.4) years and blood pressure of 117 (9)/73 (5) mmHg. Overall, high-salt diet significantly increased venular tortuosity (12.2%, p = 0.001). Other retinal parameters were not significantly different between diets. Changes in arteriolar tortuosity correlated with changes in ambulatory systolic blood pressure (r = − 0.513; p = 0.04). In conclusion, high-salt diet increases retinal venular tortuosity, and salt-induced increases in ambulatory systolic blood pressure associate with decreases in retinal arteriolar tortuosity. Besides potential eye-specific consequences, both phenomena have previously been associated with hypertension and other cardiovascular risk factors, underlining the deleterious microcirculatory effects of high salt intake.

Perindopril Reduces Arterial Pressure and Does Not Inhibit Exercise-Induced Angiogenesis in Spontaneously Hypertensive Rats.

Sympathetic activity, arteriolar structure, and angiogenesis are important mechanisms modulating hypertension and this study aimed to analyze the effects of perindopril treatment, associated or not with exercise training, on the mechanisms that control blood pressure (BP) in hypertensive rats. Spontaneously hypertensive rats (SHR) were allocated into 4 groups: 1/sedentary (S); 2/perindopril (P, 3.0 mg/kg/d); 3/trained (T); and 4/trained + perindopril (TP). Wistar rats were used as normotensive sedentary control group. SHR were assigned to undergo a treadmill training (T) or were kept sedentary. Heart rate, BP, sympathetic activity to the vessels (LF-SBP), and skeletal muscle and myocardial morphometric analyses were performed. BP was significantly lower after all 3 strategies, compared with S and was accompanied by lower LF-SBP (-76%, -53%, and -44%, for P, T, and TP, respectively). Arteriolar vessel wall cross-sectional area was lower after treatments (-56%, -52%, and -56%, for P, T, and TP, respectively), and only TP presented higher arteriolar lumen area. Capillary rarefaction was present in soleus muscle and myocardium in S group and both trained groups presented higher vessel density, although perindopril attenuated this increase in soleus muscle. Although myocyte diameter was not different between groups, myocardial collagen deposition area, higher in S group, was lower after 3 strategies. In conclusion, we may suggest that perindopril could be an option for the hypertensive people who practice exercise and need a specific pharmacological treatment to reach a better BP control, mainly because training-induced angiogenesis is an important response to facilitate blood flow perfusion and oxygen uptake and perindopril did not attenuate this response.

Coronary and cerebral metabolism-blood flow coupling and pulmonary alveolar ventilation-blood flow coupling may be disabled during acute carbon monoxide poisoning.

Current evidence indicates that the toxicity of carbon monoxide (CO) poisoning results from increases in reactive oxygen species (ROS) generation plus tissue hypoxia resulting from decreases in capillary Po2 evoked by effects of increases in blood [carboxyhemoglobin] on the oxyhemoglobin dissociation curve. There has not been consideration of how increases in Pco could influence metabolism-blood flow coupling, a physiological mechanism that regulates the uniformity of tissue Po2, and alveolar ventilation-blood flow coupling, a mechanism that increases the efficiency of pulmonary O2 uptake. Using published data, I consider hypotheses that these coupling mechanisms, triggered by O2 and CO sensors located in arterial and arteriolar vessels in the coronary and cerebral circulations and in lung intralobar arteries, are disrupted during acute CO poisoning. These hypotheses are supported by calculations that show that the Pco in these vessels can reach levels during CO poisoning that would exert effects on signal transduction molecules involved in these coupling mechanisms.NEW & NOTEWORTHY This article introduces and supports a postulate that the tissue hypoxia component of carbon monoxide poisoning results in part from impairment of physiological adaptation mechanisms whereby tissues can match regional blood flow to O2 uptake, and the lung can match regional blood flow to alveolar ventilation.

Skin auto-fluorescence as a measure of advanced glycation end-products is associated with microvascular health in patients with COPD

Background and objectivesChronic obstructive pulmonary disease (COPD) is associated with systemic inflammation and oxidative stress. These physiological processes can lead to increased formation and accumulation of advanced glycation end-products (AGEs), that can play a role in vascular complications. In this cross-sectional study, we determined the association between skin AGEs and microvascular health in patients with COPD. MethodsClinical characteristics and cardiovascular parameters, including pulmonary function, metabolic and inflammatory parameters, and blood pressure, were obtained in this observational study with patients with COPD. Skin concentrations of AGEs were assessed non-invasively by measuring skin autofluorescence (AF). Retinal vessel analysis was used as a marker of microvascular health. Results62 patients with COPD (52% males; mean age: 64.4 ± 8.4 years; mean FEV1: 45.0 ± 20.7%pred.) were analysed. Mean skin AF was 2.75 ± 0.64 arbitrary units. Skin AF in patients with COPD was negatively associated with retinal arteriolar diameter (β −0.021, 95% CI −0.040 to −0.002; p = 0.031) and arteriole-to-venular ratio (β −7.233, 95% CI −9.732 to −4.734; p < 0.001) and positively associated with retinal venular diameter (β 0.029, 95% CI 0.019 to 0.038; p < 0.001) after adjustment for sex, age, lung function, pack-years of smoking and conventional cardiovascular risk factors. ConclusionWe document for the first time that skin AF in patients with COPD is independently associated with retinal arteriolar and venular vessel diameters, biological indicators for microvascular health. This adds to the evidence that AGEs are an accessible marker of microvascular health.