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Mathematical modelling of responses of cerebral blood vessels to changing intraluminal pressure.

The authors have designed a mathematical model to investigate the influences of the physical and chemical properties of the cerebral blood vessel resistance on vessel diameter. The model is based on the way the total tension within the blood vessel walls varies due to specific ions interacting and affecting the vascular smooth muscle cells and the vascular walls. In particular, we shall model a series of calcium sites and derive a generalized equation of the diameter as a function of pressure. The model includes the action of the vascular smooth muscle cells and the elasticity of the vascular walls, the pressure exerted on the walls by the blood and the effect of alterations to their properties within the blood vessel. They are formulated in terms of three parameters: the diameter at zero pressure, the myogenic response as the pressure tends to zero and a term associated with the myogenic tone. All three parameters may be reliably extracted from diameter-pressure measurements. The model was successfully used in quantifying diameter oscillations and dynamic myogenic responses that are frequently observed both in vivo and in vitro. Finally, we tested the model on experimental data obtained from the resistance of cerebral vessels that have been isolated from rats. In particular, we have first shown that the blood vessel characteristics are such that the diameter change due to calcium ion variations is at a maximum value. Second, we have shown that blood flow affects the myogenic response and third, we can explain the affect of ATP on the vessel diameter.

Adenosine Triphosphate↗

CD34 expression patterns during early mouse development are related to modes of blood vessel formation and reveal additional sites of hematopoiesis.

CD34 is a cell surface glycoprotein that is selectively expressed within the human hematopoietic system on stem and progenitor cells, and in early blood vessels. To elucidate its functions during early blood vessel formation and hematopoiesis, we analyzed the expression patterns, in day 8 to day 10 mouse embryos, of CD34 RNA by in situ hybridization and protein by immunohistochemistry using the monclonal antibody RAM 34. Levels of expression in embryonic blood vessels were correlated with the mode of vessel formation, being high in pre-endothelial cells and in vessels forming by vasculogenesis (particularly the dorsal aortae) or angiogenesis, but low in vessels forming by coalescence (the cardinal veins). CD34+ erythroid cells, presumably of yolk sac origin, were present in the liver of day 10 embryos; at the same stage, putative definitive hematopoietic cells, strongly CD34+, were present in the para-aortic mesenchyme. Possible sites of hemangioblastic differentiation were detected in the form of CD34+ endothelium-attached hematopoietic cells in the dorsal aorta and in two previously unreported locations, the proximal umbilical and vitelline arteries. These observations suggest functions for CD34 in relation to specific modes of blood vessel formation, and a hemangioblastic role in both embryonic and extraembryonic sites.

Allantois↗

Overexpression of semicarbazide sensitive amine oxidase in the cerebral blood vessels in patients with Alzheimer's disease and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Semicarbazide sensitive amine oxidase (SSAO) metabolizes oxidative deamination of primary aromatic and aliphatic amines, and, in the brain, it is selectively expressed in blood vessels. SSAO expression is examined, by immunohistochemistry with a purified polyclonal antibody to SSAO from bovine lung, in the brains of subjects with Alzheimer disease (AD; n=10), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; n=2), and age-matched controls (n=8). SSAO immunoreactivity is restricted to meningeal and parenchymal blood vessels in control and diseased brains. Yet, a marked and selective increase in SSAO immunoreactivity occurs in association with betaA4 vascular amyloid deposits in patients with AD, and in the vicinity of the typical granular deposits in the blood vessels of gray and white matter in patients with CADASIL. Oxidative deamination of primary aromatic and aliphatic amines by SSAO produces ammonia, hydrogen peroxide and the corresponding aldehyde. Moreover, increased SSAO immunoreactivity is associated with increased Cu/Zn superoxide dismutase 1 expression restricted to abnormal blood vessels in diseased brains. Therefore, it is suggested that increased SSAO expression is a source of oxidative stress in the blood vessel wall in AD and CADASIL.

Aged↗

Arterial wall imaging: evaluation with 16-section multidetector CT in blood vessel phantoms and ex vivo coronary arteries.

PURPOSE: To evaluate the diagnostic performance of 16-section multidetector computed tomography (CT) for assessment of plaques in phantoms and ex vivo coronary arteries, with intravascular ultrasonography (US) and optical coherence tomography (OCT) as reference standards. MATERIALS AND METHODS: Research protocol was HIPAA compliant and approved by institutional review board, without informed consent required. Blood vessel and lesion composition phantoms and ex vivo coronary arteries were imaged with 16-section CT. Wall areas of phantoms and ex vivo coronary arteries were measured with multidetector CT and intravascular US. Sensitivity and specificity for lipid detection were determined in lesion composition phantoms. CT numbers of blood vessel wall were determined in ex vivo coronary arteries and compared with lesion classification results from OCT. Agreement in dimensional measurements was compared (paired t tests). CT numbers within blood vessel wall of CT cross sections classified as lipid rich, fibrous, and calcified at OCT were compared (Kruskal-Wallis tests). RESULTS: Mean blood vessel wall areas measured with CT and US in phantoms were 9.2 mm(2) +/- 1.8 (standard deviation) and 10.4 mm(2) +/- 3.4 (bias, -1.3 mm(2) +/- 3.1; P < .05), respectively. Mean blood vessel wall areas measured in ex vivo coronary arteries with CT and US were 10.9 mm(2) +/- 4.1 and 9.1 mm(2) +/- 3.1 (bias, 1.8 mm(2) +/- 3.0; P < .001), respectively. Sensitivity and specificity of 93% and 92%, respectively, for identification of lipid-rich lesions were observed in lesion composition phantoms. Mean CT numbers in blood vessel wall of ex vivo coronary arteries identified at OCT as predominantly lipid rich, fibrous, and calcified were 29 HU +/- 43, 101 HU +/- 21, and 135 HU +/- 199, respectively (P < .001). CONCLUSION: Determination of composition of individual plaques from attenuation values can be more challenging because of overlapping values for different tissue types.

Coronary Angiography↗

Endothelin is blood vessel selective: studies on a variety of human and dog vessels in vitro and on regional blood flow in the conscious rabbit.

1. Endothelin (Et), a vasoconstrictor peptide, was 5-10-fold more potent (lower EC50) on isolated ring segments of large veins than on large arteries removed from dog coronary, mesenteric, femoral, renal and internal mammary vasculature and from the human internal mammary pedicle. 2. In the dog large coronary artery, Et (10-30 nmol/L) caused transient relaxations partway through the generation of a concentration-contraction curve. These relaxations were endothelium dependent. 3. In conscious rabbits treated with mecamylamine, Et (0.025-0.4 nmol/kg) caused a marked rise in renal vascular resistance but hindquarter vasodilation. Under the same conditions angiotensin II constricted both beds. 4. These studies suggest that Et is vascular bed and large vein selective in activity. It did not appear to be selective for large or small coronary arteries in vitro.

Animals↗

VEGF signaling is required for the assembly but not the maintenance of embryonic blood vessels.

Here we investigated the importance of vascular endothelial growth factor (VEGF) signaling to the de novo formation of embryonic blood vessels, vasculogenesis, as opposed to the maintenance of blood vessels. We found that antagonizing the activity of the VEGF signaling pathway by using soluble VEGF receptor 1 (sFlt1) or VEGF antibodies inhibited vasculogenesis that occurs in embryos and in cultures of 7.5 days postcoitus prevascular mesoderm. Antagonist treatment resulted in the formation of clusters of endothelial cells not normally observed during vasculogenesis. In contrast, when embryos with established vasculatures or cultures of vascularized mesoderm were treated with sFlt1 or VEGF antibodies, no discernible alterations to the preexisting blood vessels were observed. These observations indicate that, although VEGF signaling is required to promote the mesenchymal to epithelial transition by which angioblasts assemble into nascent endothelial tubes, it is not required by endothelial cells to maintain their organization as an endothelium.

Allantois↗

Cellular abnormalities of blood vessels as targets in cancer.

Tumor blood vessels have multiple structural and functional abnormalities. They are unusually dynamic, and naturally undergo sprouting, proliferation, remodeling or regression. The vessels are irregularly shaped, tortuous, and lack the normal hierarchical arrangement of arterioles, capillaries and venules. Endothelial cells in tumors have abnormalities in gene expression, require growth factors for survival and have defective barrier function to plasma proteins. Pericytes on tumor vessels are also abnormal. Aberrant endothelial cells and pericytes generate defective basement membrane. Angiogenesis inhibitors can stop the growth of tumor vessels, prune existing vessels and normalize surviving vessels. Loss of endothelial cells is not necessarily accompanied by simultaneous loss of pericytes and surrounding basement membrane, which together can then provide a scaffold for regrowth of tumor vessels. Rapid vascular regrowth reflects the ongoing drive for angiogenesis and bizarre microenvironment in tumors that promote vascular abnormalities and thereby create therapeutic targets.

Angiogenesis Inhibitors↗

Phenotype of normal cutaneous microvasculature. Immunoelectron microscopic observations with emphasis on the differences between blood vessels and lymphatics.

The lymphatic system has been poorly characterized in comparison to the blood vessels. We investigated the expression of microvasculature markers in cutaneous lymphatics and blood microvessels in normal skin. Scrotal skin was chosen because of its high density of both types of microvessels. A pre-embedding peroxidase-conjugated immunoelectron microscopy technique was used, allowing both the visualization of the lymph and blood vessels and their immunohistochemical staining. The markers studied included endothelial antigens (recognized by PAL-E, EN-4, and von Willebrand factor/factor VIII-related antigen), structural molecules of the vascular wall (alpha-smooth muscle actin, heparan sulfate proteoglycan, collagen type IV), and adhesion molecules (endothelial leukocyte adhesion molecule-1 [E-selectin], intercellular adhesion molecule-1 [ICAM-1], platelet endothelial adhesion molecule-1 [PECAM-1], vascular cell adhesion molecule-1 [VCAM-1]). It is shown that lymphatics of normal skin are phenotypically different from blood microvasculature, only weakly expressing endothelial markers (EN-4+, von Willebrand factor/factor VIII-related antigen +/-, PAL-E-), mural markers (alpha-smooth muscle actin-, heparan sulfate proteoglycan-, collagen type IV+) and do not express the studied adhesion molecules except PE-CAM-1 (E-selectin-, ICAM-1-, PECAM-1+, VCAM-1-). The results were substantiated by a double-labeling immunoelectron microscopic technique, which facilitates detection and assessment of microvascular segments. By this technique, collagen type IV, recognized by a peroxidase-labeled 2nd antibody, stains the basal lamina by a linear pattern, whereas a second optional epitope is visualized as grains by a silver-enhanced ultra-small gold-conjugated antibody. Our study shows that not only morphology but also antigenic phenotype of lymphatics differs significantly from blood vessels.

Capillaries↗

Freeze-fracture analysis of the interendothelial junctions in the blood vessels of the iris in Macaca mulatta.

The interendothelial cell junctions in the blood vessels of the rhesus monkey iris were examined by both conventional electron microscopy and the freeze-fracturing technique. Endothelial cells of iris blood vessels were joined by two types of intercellular junctions: zonular tight junctions and gap junctions. The zonulae occludentes were represented by a complex network of branching and anastomosing strands that remained preferentially associated with the E fracture face. They varied in complexity from a single strand to eight or more but usually consisted of from two to four strands. Small gap junctions were inserted within the tight junctional network. Junctions similar to those typical of muscular and visceral venules were absent. Thus the intercellular clefts of all iris vessels are closed by zonulae occludentes that exhibit a degree of complexity intermediate between the endothelial junctions of the cerebral cortex and those of striated muscles and viscera. This finding strongly suggests that the blood vessels of the iris participate only minimally in aqueous humor dynamics.

Animals↗

Sonographic characteristics of small cerebral blood vessels. An in vivo and postmortem study.

The ultrasound appearance of small cerebral blood vessels was investigated with in vivo and postmortem sonography. Linear echoes corresponding in distribution to small branches of major cerebral blood vessels, particularly deep medullary veins, were seen during cranial sonography of living neonates, neonatal postmortem brains, and adult postmortem brains following intravascular injection of a barium sulfate-gelatin suspension. Ease of visualization of the echoes was angle dependent, a phenomenon termed anisotropy. When imaged in cross-section, these reflectors appeared as tiny, closely spaced dots, demonstrating their tubular nature. Additionally, the barium-injected adult postmortem specimens were studied by computed tomography and plain-film radiography, enabling correlation between radiography and sonography. This study demonstrates that small branches of the major intracranial blood vessels can be imaged as linear echoes and closely spaced dots by high-resolution sonography. It is important to recognize the vascular origin of these echoes to avoid the pitfall of misinterpreting them as originating from pathologic processes such as periventricular leukomalacia.

Adult↗

Use of ultrasound for noninvasive study of blood vessel responsiveness.

To provide a noninvasive means for studying individual macroscopic blood vessels, an ultrasound scanner was modified to provide a recording of blood vessel diameter. The instrument has A- and B-modes of signal display. The B-mode is used to position the probe and the A-mode to measure vessel diameter. The A-mode has two electronic gates for tracking the echo from each of two structures, i.e., near and far wall of vessel. The front gate was modified to pick up the falling rather than rising edge of a peak generated by the vessel wall. An analog signal proportional to the distance between gates was derived for recording with a strip-chart recorder. Probe holders were constructed to optimize positioning and holding of probe. Stability was excellent (reading varied 0.05 mm over 1 h). Axial resolution was between 0.3 and 0.73 mm. Discrepancy of measurements of plastic tubing made by ocular and ultrasound varied from 1.1 to 4.6%. Discrepancy with lightly fixed vessels was 2.7-8.2%. Ex vivo measurements on vessels with viable smooth muscle were more variable, perhaps because of actual change during measurements. Changes in vessel diameter induced by change in hydrostatic pressure and exposure to histamine were recorded.

Animals↗

[Establishment of biopanning model of phage display peptide library in the blood vessels of excised human osteosarcoma vasculature and its significance].

OBJECTIVE: To establish an in vivo biopanning model of phage display peptide library in the blood vessels contained in surgically removed human osteosarcoma. METHOD: In 28 patients with osteosarcoma, digital subtraction angiography (DSA) of the involved limb was performed preoperatively to understand the approximate status of the arteries in the tumors. The tumors were then surgically removed and carefully trimmed, perfused via a simulated Langendorff perfusion apparatus with the indexes as the pH value, temperature and O2 partial pressure monitored in the blood vessels. A 12-meres phage display peptide library was biopanned to isolate peptides capable of homing specifically to the excised osteosarcoma. RESULTS: In vivo biopanning models were successfully established in all the excised tumors, which could be directly used in perfusion experiment and the indexes monitored in the blood vessels in the tumors were comparable to those of living tissues. Some high-affinity peptides specific to the blood vessels in osteosarcoma were obtained with the motif of RLTR. CONCLUSION: In vivo biopanning model simulating the Langendorff perfusion apparatus can be easily established which is instrumental for the application of phage display technology in human living tissues and may facilitate the study of targeted chemotherapy of osteosarcoma.

Adolescent↗

Tissue engineering a blood vessel substitute: the role of biomechanics.

The engineering of a functional blood vessel substitute has for a quarter of a century been a "holy grail" within the cardiovascular research community. Such a substitute must exhibit long term patency, and the critical issues in this area in many ways are influenced by biomechanics. One of the requirements is that it must be non-thrombogenic, which requires an "endothelial-like" inner lining. It also must have mechanical strength, i.e. a burst pressure, sufficient to operate at arterial pressures. Ideally, however, it must be more than this. It also must have viscoelastic properties that match those of the native vessel being replaced. Finally, if it is to be able to adapt to changing blood flow conditions, it must exhibit vasoactivity, a function which in and of itself can be viewed as biomechanical in nature. To achieve this requires having, as part of the construct, vascular smooth muscle cells, which are contractile in nature and oriented in a circumferential direction. Only if an engineered blood vessel substitute possesses all of these functional characteristics, can one say that the functionality exhibited by a native vessel is being mimicked.

Artificial Organs↗

Gene transfer by viral vectors into blood vessels in a rat model of retinopathy of prematurity.

AIMS: To test the feasibility of gene transfer into hyaloid blood vessels and into preretinal neovascularisation in a rat model of retinopathy of prematurity (ROP), using different viral vectors. METHODS: Newborn rats were exposed to alternating hypoxic and hyperoxic conditions in order to induce ocular neovascularisation (ROP rats). Adenovirus, herpes simplex, vaccinia, and retroviral (MuLV based) vectors, all carrying the beta galactosidase (beta-gal) gene, were injected intravitreally on postnatal day 18 (P18). Two sets of controls were also examined: P18 ROP rats injected with saline and P18 rats that were raised in room air before the viral vectors or saline were injected. Two days after injection, the rats were killed, eyes enucleated, and beta-gal expression was examined by X-gal staining in whole mounts and in histological sections. RESULTS: Intravitreal injection of the adenovirus and vaccinia vectors yielded marked beta-gal expression in hyaloid blood vessels in the rat ROP model. Retinal expression of beta-gal with these vectors was limited almost exclusively to the vicinity of the injection site. Injection of herpes simplex yielded a punctuate pattern of beta-gal expression in the retina but not in blood vessels. No significant beta-gal expression occurred in rat eyes injected with the retroviral vector. CONCLUSIONS: Adenovirus is an efficient vector for gene transfer into blood vessels in an animal model of ROP. This may be a first step towards utilising gene transfer as a tool for modulating ocular neovascularisation for experimental and therapeutic purposes.

Animals↗

Analysis of the wall permeability of blood vessels in the rat mesentery.

The transport of fluorescent tracer molecules of various molecular weights (MW 340-300,000) within the blood vessels and through the vessel walls into the perivascular tissue of the rat mesentery was studied microscopically. Using a highly sensitive TV-tube the fluorescence intensities were transformed into video signals and recorded for subsequent analysis. The results show that small molecules, such as the water-soluble dye fluorescein-sodium ( F1Na ) (MW 340) can pass through the wall of all blood vessels with minimal delay, whereas the passage of large molecules, such as the serum proteins (MW greater than 60,000), depends very strongly on the diameter of the vessels and on the medium in which the mesentery is embedded during the observation. In this respect, no difference was registered between vessels of the arterial and of the venous part of the microcirculation. The large serum protein molecules moved through the blood vessel walls at specific leakage points. The small dye molecules, however, traversed the wall uniformly along the entire length of the blood vessel. The small-molecule behavior could be described by a passive diffusion model with a cylindrical diffusion source.

Animals↗

Changes in the rheological properties of blood vessel tissue remodeling in the course of development of diabetes.

Rheological properties of blood vessels are expected to change in disease process if the structure of the vessel wall changes. This is illustrated in diabetes, which can be induced in rat by a single injection of Streptozocin. One of the rheological properties of the blood vessel is the stress-strain relationship. The nonlinear stress-strain relationship of arteries is best expressed as derivations of a strain-energy function. In this paper, the stress-strain relations are measured and the coefficients in the strain energy function of arteries are determined for diabetic and control rats. The meaning of these coefficients are explained. The influence of diabetes on the elastic property of the arteries is expressed by the changes of these coefficients. A point of departure of the present paper from all other blood vessel papers published so far is that all strains used here are referred to the zero-stress state of the arteries, whereas all other papers refer strains to the no-load state. The existence of a large difference between the zero-stress state and no-load state of arteries is one of our recent findings. We have explained that the use of zero-stress state as a basis of strain measurements reveals that the in vivo circumferential stress distribution is quite uniform in the vessel wall at the homeostatic condition. It also makes the strain energy function much more accurate than those in which the residual stress is ignored. Using these new results, the stress and strain distribution in normal and diabetic arteries are presented.

Animals↗

[Experimental modeling of the blood vessels magnetic embolization].

The embolization of blood vessels is used on a large scale: the method is applied in different diseases, in the ablation of organs, but especially in tumor necrosis. The embolization can be also magnetic, if the embolus is obtained through the deposit in the vessel of magnetic nano or microparticles in the presence of an external magnetic field. The objective of our study was the modeling of the magnetic embolization using amorphous magnetic microspheres that have strong magnetic properties and are biocompatible. Experimental tests were made in order to observe the building of the magnetic embolus inside a thin spiral tube and to determine the influence of some parameters on the efficiency of occlusions: the dimensions of magnetic microspheres (1-300 mm), the debit of the liquid (4.66 - 16.5 ml/min), the viscosity of the carrier liquid (1.007 - 7.34 cSt), the direction and the intensity of the external magnetic field (340 - 600 Gs), the shape of the tube and the linear length of the deposit (5 - 50 mm). Under pre-established experimental conditions the efficiencies of occlusions were between 67% and 100%.

Blood Vessels↗

[Cancer metastasis and blood vessels].

The ultrastructural features on interaction of tumor cells and blood vessels in the process of hematogenous metastasis formation by Yoshida sarcoma, 5 strains of Yoshida rat ascites hepatoma, murine B16 melanoma variant sublines, and others have been described and illustrated. Intravasation and extravasation of tumor cells appeared to be similar cell biological phenomenon, in which two different ways were involved: 1) tumor cells migrated through the pores in the vascular walls which were produced by direct actions of tumor cells, and 2) endothelial cell cytoplasms enclosed the tumor cells neighboring to the vascular walls and as a result intravascular or extravascular tumor cell movement occurred. Tumor cells arrested in a target organ were in close contact with vascular endothelial cells and further with basement membrane when the endothelial linings were removed. In some regions we found junction-like structures between these cells. This appeared to be corresponding to the lodgement of tumor cells in the target organ. Extravasated tumor cells produced three different features of metastatic lesions in the combination of tumor strain and the organ affected; formation of tumor nodules accompanying neovasculature, spreading of tumor cells along the perivascular tissue of an organ, and diffuse infiltration of tumor cells in an organ. It has been discussed that these features in every process mentioned above are determined by specific interaction of tumor cells and host cellular components, especially blood vessels including tumor neovasculature.

Animals↗