"Sausage-string" appearance of arteries and arterioles can be caused by an instability of the blood vessel wall

Vascular damage induced by acute hypertension is preceded by a peculiar pattern where blood vessels show alternating regions of constrictions and dilations ("sausages on a string"). The pattern occurs in the smaller blood vessels, and it plays a central role in causing the vascular damage. A related vascular pattern has been observed in larger vessels from several organs during angiography. In the larger vessels the occurrence of the pattern does not appear to be related to acute hypertension. A unifying feature between the phenomenon in large and small vessels seems to be an increase in vascular wall tension. Despite much research, the mechanisms underlying the sausage pattern have remained unknown. Here we present an anisotropic model of the vessel wall and show that the sausage pattern can arise because of an instability of the vessel wall. The model reproduces many of the key features observed experimentally. Most importantly, it suggests that the "sausaging" phenomenon is neither caused by a mechanical failure of the vessel wall due to a high blood pressure nor is it due to standing pressure waves caused by the beating of the heart. Rather, it is the expression of a general instability phenomenon. Experimental data suggest that the structural changes induced by the instability may cause secondary damage to the wall of small arteries and arterioles in the form of endothelial hyperpermeability followed by local fibrinoid necrosis of the vascular wall.     

The Role of Preventing Nitric Oxide Deficiency in the Antihypertensive Effect of Adaptation to Hypoxia

Shortage of endothelial nitric oxide (NO) manifested as decreased daily urinary excretion of nitrate and nitrite as well as attenuated endothelium-dependent relaxation of conduit and resistance vessels progresses with age-related increase of blood pressure (BP) in stroke-prone spontaneously hypertensive rats (SHRSP). Simultaneous NO-dependent suppression of vascular contractions is, apparently, due to the inducible NO synthase activity in vascular smooth muscle specific for spontaneously hypertensive rat. The adaptation of rats to hypobaric hypoxia initiated at early hypertensive stage (at the age of 5–6 weeks) decelerates hypertension progress. The antihypertensive effect of the adaptation was accompanied by stimulation of endothelial NO synthesis and prevention of impaired NO-dependent response in isolated blood vessels. Nitric oxide stores were formed in the vascular wall of SHRSP and WKY rats at the same time. The obtained data indicate that the correction of endothelial NO deficiency plays a significant role in the antihypertensive effect of adaptation to hypoxia.     

The microcirculatory bed of the human heart

Using a complex approach in studying microcirculatory bed of the human heart, possibilities of scanning electron microscopy of corrosive preparations, those of silver nitrate impregnation after V. V. Kuprianov are demonstrated. The silver nitrate impregnation makes it possible to study the wall structure of the microcirculatory pathways, to analyse arrangement of nuclei in the endothelial and muscle cells of the microcirculatory links, to reveal together with the vessels the surrounding tissues. Scanograms of the corrosive preparations of the arterioles demonstrate "circulatory strips", that are absent in the venular part. The relief of the luminal casts of the microcirculatory bed vessels in the human heart is presented as impresses of nuclei of the endothelial and smooth muscle cells. Peculiarities in form and distribution of these nuclei in various links of the microbed are demonstrated.     

Reflex regulation of the circulation after stimulation of cardiac receptors by prostaglandins

Prostaglandins (PGs) are potent vasoactive substances that may participate in the control of coronary blood flow, platelet aggregation, and inflammation. An important action of PGs may be the stimulation of c fibers in general and vagal cardiac c fibers in particular. The Bezold-Jarisch reflex after intracoronary injection of Veratrum alkaloids is very similar to the vagal bradycardia elicited by stimulation of cardiac PG synthesis or injection of prostacyclin (PGI2). The characteristic features of this reflex are 1) stimulation of c fibers, 2) inferoposterior wall location of receptors, 3) vagal afferents, 4) vagal efferents to the heart, 5) sympathetic efferents to peripheral blood vessels, and 6) interaction with other reflexes. Vagal cardiac c fibers are activated by intracoronary injections of PGI2 or arachidonic acid, resulting in a vagal reflex bradycardia and hypotension due to withdrawal of peripheral alpha-adrenergic tone to resistance vessels. The cardiac receptors are located predominantly in the inferoposterior wall of the left ventricle. When stimulated by PGs, cardiac receptors may also modify the regulation of arterial pressure by the baroreflexes, altering the inverse relationship between systemic arterial pressure and heart rate. Thus, there is a striking parallelism between the veratridine-induced Bezold-Jarisch reflex and PG-induced cardiac reflexes, although the physiological and clinical significance of these reflexes remains to be determined.     

Differentiation of stem/progenitor cells into vascular cells in response to fluid mechanical forces

Vascular functions are regulated not only by chemical mediators, such as hormones, cytokines, and neurotransmitters, but by mechanical hemodynamic forces generated by blood flow and blood pressure. The mechanical force-mediated regulation is based on the ability of vascular cells, including endothelial cells and smooth muscle cells, to recognize fluid mechanical forces, i.e., the shear stress produced by flowing blood and the cyclic strain generated by blood pressure, and to transmit the signals into the cell interior, where they trigger cell responses that involve changes in cell morphology, cell function, and gene expression. Recent studies have revealed that immature cells, such as endothelial progenitor cells (EPCs) and embryonic stem (ES) cells, as well as adult vascular cells, respond to fluid mechanical forces. Shear stress and cyclic strain promote the proliferation and differentiation of EPCs and ES cells into vascular cells and enhance their ability to form new vessels. Even more recently, attempts have been made to apply fluid mechanical forces to EPCs and ES cells cultured on polymer tubes and develop tissue-engineered blood vessel grafts that have a structure and function similar to that of blood vessels in vivo. This review summarizes the current state of knowledge concerning the mechanobiological responses of stem/progenitor cells and its potential applications to tissue engineering.     

Vascular wall resident progenitor cells: a source for postnatal vasculogenesis

Here, we report the existence of endothelial precursor (EPC) and stem cells in a distinct zone of the vascular wall that are capable to differentiate into mature endothelial cells, hematopoietic and local immune cells, such as macrophages. This zone has been identified to be localized between smooth muscle and adventitial layer of human adult vascular wall. It predominantly contains CD34-positive (+) but CD31-negative (-) cells, which also express VEGFR2 and TIE2. Only few cells in this zone of the vascular wall are positive for CD45. In a ring assay using the fragments of human internal thoracic artery (HITA), we show here that the CD34+ cells of the HITA-wall form capillary sprouts ex vivo and are apparently recruited for capillary formation by tumor cells. New vessels formed by these vascular wall resident EPCs express markers for angiogenically activated endothelial cells, such as CEACAM1, and also for mature endothelial cells, such as VE-cadherin or occludin. Vascular wall areas containing EPCs are found in large and middle sized arteries and veins of all organs studied here. These data suggest the existence of a ;vasculogenic zone' in the wall of adult human blood vessels, which may serve as a source for progenitor cells for postnatal vasculogenesis, contributing to tumor vascularization and local immune response.     

Ultrastructure of the Circulatory System of the Phoronid Phoronopsis harmeri Pixell, 1912. 2. Main vessels

The ultrastructure of the wall of the main blood vessels of the phoronid Phoronopsis harmeri is described. The walls of the lophophoral and left lateral vessels consist of myoepithelial cells of the coelomic lining (peritoneal cells), a thin basal lamina, and an incomplete endothelial lining. In the head region of the body, the wall of the medial vessel consists of myoepithelial cells of the coelomic lining (peritoneal cells), a basal lamina, and true muscular endothelial cells. The anterior part of the medial vessel functions as the heart. In the anterior part of the body, the medial vessel wall consists of five layers: the external nonmuscular coelothelium, a layer of the extracellular matrix, the internal muscular coelothelium, an internal layer of the extracellular matrix, and an incomplete endothelial lining. The complicated structure of the medial vessel wall may be explained by the superimposition of the lateral mesentery on the ordinary vessel wall.     

New emerging developments of platelets in transfusion medicine

Autologous platelet-rich plasma (PRP) or platelet gel (PG) has been widely used in clinical treatment. Allogeneic PRP or PG may also become a safe and effective alternative method. In this study, two cases with giant thoracic aortic aneurysm were reported where massive doses of allogeneic PG were used to spray the thoracic aortic aneurysm wall suture wrapped in artificial blood vessels, tumors blood vessel wall anastomotic site, and incision site of surgical operation. The volumes of 220 mL and 250 mL PG were applied on two patients respectively, to clot bleeding and decrease the mediastinal and pericardial drainage days after operation. The drainage tubes were pulled out on the 4^th day after operation. The patients were transferred from ICU to a cardiothoracic surgery ward on the 4^th and 5^th day respectively. This study suggests that allogeneic platelet concentrate, as a source of PRP to prepare PG, may be used to promote and help the clotting and wound healing on surgical operation.     

Hedgehog signaling is essential for endothelial tube formation during vasculogenesis

During embryonic development, the first blood vessels are formed through the aggregation and subsequent assembly of angioblasts (endothelial precursors) into a network of endothelial tubes, a process known as vasculogenesis. These first vessels generally form in mesoderm that is adjacent to endodermal tissue. Although specification of the angioblast lineage is independent of endoderm interactions, a signal from the endoderm is necessary for angioblasts to assemble into a vascular network and to undergo vascular tube formation. In this study, we show that endodermally derived sonic hedgehog is both necessary and sufficient for vascular tube formation in avian embryos. We also show that Hedgehog signaling is required for vascular tube formation in mouse embryos, and for vascular cord formation in cultured mouse endothelial cells. These results demonstrate a previously uncharacterized role for Hedgehog signaling in vascular development, and identify Hedgehog signaling as an important component of the molecular pathway leading to vascular tube formation.     

Essential role of the coxsackie- and adenovirus receptor (CAR) in development of the lymphatic system in mice

The coxsackie- and adenovirus receptor (CAR) is a cell adhesion molecule predominantly associated with epithelial tight junctions in adult tissues. CAR is also expressed in cardiomyocytes and essential for heart development up to embryonic day 11.5, but not thereafter. CAR is not expressed in vascular endothelial cells but was recently detected in neonatal lymphatic vessels, suggesting that CAR could play a role in the development of the lymphatic system. To address this, we generated mice carrying a conditional deletion of the CAR gene (Cxadr) and knocked out CAR in the mouse embryo at different time points during post-cardiac development. Deletion of Cxadr from E12.5, but not from E13.5, resulted in subcutaneous edema, hemorrhage and embryonic death. Subcutaneous lymphatic vessels were dilated and structurally abnormal with gaps and holes present at lymphatic endothelial cell-cell junctions. Furthermore, lymphatic vessels were filled with erythrocytes showing a defect in the separation between the blood and lymphatic systems. Regionally, erythrocytes leaked out into the interstitium from leaky lymphatic vessels explaining the hemorrhage detected in CAR-deficient mouse embryos. The results show that CAR plays an essential role in development of the lymphatic vasculature in the mouse embryo by promoting appropriate formation of lymphatic endothelial cell-cell junctions.     

New morphological aspects of blood islands formation in the embryonic mouse hearts

Vasculogenesis in embryonic hearts proceeds by formation of aggregates consisting of erythroblasts and endothelial cells. These aggregates are called blood-islands or blood-island-like structures. We aimed to characterize blood islands in mouse embryonic hearts at stages spanning from 11 dpc through 13 dpc, i.e. prior to the establishment of the coronary circulation. Our observations suggested that there are two types of blood islands. One formed by migrating nucleated erythroblasts, which associated with migrating endothelial cell and the second by in situ emergence of two kinds of cells belonging to separate populations: one resembling an erythroblast progenitor and the second resembling an endothelial-cell progenitor. The subepicardial blood islands contain nucleated erythroblasts, undifferentiated mesenchymal cells, platelets, and early lymphocytes. The subepicardial blood islands resemble vesicles with protruding prongs directed toward the myocardium. Ahead of the prongs, angiogenic sprouting and degradation of fibronectin is observed. Vesicles gradually change their shape from spherical to tubular at 13 dpc and grow and extend along the interventricular sulcuses forming vascular tubes. We presume that the vascular tubes located within the interventricular sulcuses are precursors of coronary veins. Our data seems to indicate that embryonic heart vasculogenesis is accompanied by hematopoiesis     

The neural tube patterns vessels developmentally using the VEGF signaling pathway

Embryonic blood vessels form in a reproducible pattern that interfaces with other embryonic structures and tissues, but the sources and identities of signals that pattern vessels are not well characterized. We hypothesized that the neural tube provides vascular patterning signal(s) that direct formation of the perineural vascular plexus (PNVP) that encompasses the neural tube at mid-gestation. Both surgically placed ectopic neural tubes and ectopic neural tubes engineered genetically were able to recruit a vascular plexus, showing that the neural tube is the source of a vascular patterning signal. In mouse-quail chimeras with the graft separated from the neural tube by a buffer of host cells, graft-derived vascular cells contributed to the PNVP, indicating that the neural tube signal(s) can act at a distance. Murine neural tube vascular endothelial growth factor A (VEGFA) expression was temporally and spatially correlated with PNVP formation, suggesting it is a component of the neural tube signal. A collagen explant model was developed in which presomitic mesoderm explants formed a vascular plexus in the presence of added VEGFA. Co-cultures between presomitic mesoderm and neural tube also supported vascular plexus formation, indicating that the neural tube could replace the requirement for VEGFA. Moreover, a combination of pharmacological and genetic perturbations showed that VEGFA signaling through FLK1 is a required component of the neural tube vascular patterning signal. Thus, the neural tube is the first structure identified as a midline signaling center for embryonic vascular pattern formation in higher vertebrates, and VEGFA is a necessary component of the neural tube vascular patterning signal. These data suggest a model whereby embryonic structures with little or no capacity for angioblast generation act as a nexus for vessel patterning.     

Vascular endothelium (review). I. General morphology. 2B: phylogenesis of the vascular endothelium

The phylogenetic descent of vascular endothelium from mesenchyme--derived precursors is described related to the development of a vessel--bound microcirculation. Endothelial precursors in primitive animals may have migrated into tissue clefts gradually forming vascular tubes. True microcirculatory vessels at first appear in the nemertines, a closed vascular system is present in some annelids whereas in arthropods an open lacunar system predominates. The first appearance of true endotheliocytes is under discussion; the author gives some evidence that it is present already in some annelids. Precursor of the endothelial wall of vessels may be the so called "Leydig's membrane", covered with amoebocytes and other mesenchymal cells. The molluscs exhibit many variants of endothelium. In the fishes, the vascular system begins to split into a blood and a lymphatic system. Obviously the specialization of endothelium correlates with the level of evolution. Despite the complicated course, the evolution of endothelium may be regarded as monophyletic.     

A massive dose of allogeneic platelet gel for wound hemostatic therapy on patients with giant thoracic aortic aneurysm: report of 2 cases

Autologous platelet-rich plasma (PRP) or platelet gel (PG) has been widely used in clinical treatment. Allogeneic PRP or PG may also become a safe and effective alternative method. In this study, two cases with giant thoracic aortic aneurysm were reported where massive doses of allogeneic PG were used to spray the thoracic aortic aneurysm wall suture wrapped in artificial blood vessels, tumors blood vessel wall anastomotic site, and incision site of surgical operation. The volumes of 220 mL and 250 mL PG were applied on two patients respectively, to clot bleeding and decrease the mediastinal and pericardial drainage days after operation. The drainage tubes were pulled out on the 4^th day after operation. The patients were transferred from ICU to a cardiothoracic surgery ward on the 4^th and 5^th day respectively. This study suggests that allogeneic platelet concentrate, as a source of PRP to prepare PG, may be used to promote and help the clotting and wound healing on surgical operation.     

Tissue engineering of blood vessels with endothelial cells differentiated from mouse embryonic stem cells

Endothelial cells (TEC3 cells) derived from mouse embryonic stem (ES) cells were used as seed cells to construct blood vessels. Tissue engineered blood vessels were made by seeding 8 X 106 smooth muscle cells (SMCs) ob-tained from rabbit arteries onto a sheet of nonwoven polyglycolic acid (PGA) fibers, which was used as a biode-gradable polymer scaffold. After being cultured in DMEM medium for 7 days in vitro, SMCs grew well on the PGA fibers, and the cell-PGA sheet was then wrapped around a silicon tube, and implanted subcutaneously into nude mice. After 6～8 weeks, the silicon tube was replaced with another silicon tube in smaller diameter, and then the TEC3 cells (endothelial cells differentiated from mouse ES cells) were injected inside the engineered vessel tube as the test group. In the control group only culture medium was injected. Five days later, the engineered vessels were harvested for gross observation, histological and immunohistochemical analysis. The preliminary results demonstrated that the SMC-PGA construct could form a tubular structure in 6-8 weeks and PGA fibers were completely degraded. Histological and immunohistochemical analysis of the newly formed tissue revealed a typical blood vessel structure, including a lining of endothelial cells (ECs) on the lumimal surface and the presence of SMC and collagen in the wall. No EC lining was found in the tubes of control group. Therefore, the ECs differentiated from mouse ES cells can serve as seed cells for endothelium lining in tissue engineered blood vessels.     

Constitutive over-expression of VEGF results in reduced expression of Hand-1 during cardiac development in Xenopus

During heart development, various signaling cascades are tightly regulated in a stage- and region-dependent manner. Vascular endothelial growth factor (VEGF) is one of the important molecules required for both vascular development and cardiac morphogenesis. VEGF receptors are present in the embryonic heart, so we focused on heart formation in VEGF-over-expressing Xenopus embryos. Over-expression of VEGF(170) caused disorganized vessels, while the expression of an endothelial marker, Tie-2, was increased. The embryo's heart was distinctly larger than that of control, and showed abnormal morphology. Histological analysis of these embryos showed failure of heart looping. In situ hybridization with Hand-1, which controls intrinsic morphogenetic pathways, revealed that the expression level of Hand-1 was decreased in the heart region. These results suggest that increased VEGF(170) levels disturb Hand-1 expression in the region required for normal heart morphogenesis. VEGF expression level may be important in heart morphology during embryonic development.     

Effects of arterial wall stress on vasomotion

Smooth muscle and endothelial cells in the arterial wall are exposed to mechanical stress. Indeed blood flow induces intraluminal pressure variations and shear stress. An increase in pressure may induce a vessel contraction, a phenomenon known as the myogenic response. Many muscular vessels present vasomotion, i.e., rhythmic diameter oscillations caused by synchronous cytosolic calcium oscillations of the smooth muscle cells. Vasomotion has been shown to be modulated by pressure changes. To get a better understanding of the effect of stress and in particular pressure on vasomotion, we propose a model of a blood vessel describing the calcium dynamics in a coupled population of smooth muscle cells and endothelial cells and the consequent vessel diameter variations. We show that a rise in pressure increases the calcium concentration. This may either induce or abolish vasomotion, or increase its frequency depending on the initial conditions. In our model the myogenic response is less pronounced for large arteries than for small arteries and occurs at higher values of pressure if the wall thickness is increased. Our results are in agreement with experimental observations concerning a broad range of vessels.     

Eicosanoid production by the coronary microvascular endothelium

Cultured rabbit coronary microvessel endothelial (RCME) cells have been used as an in vitro model to study the regulation of microvascular endothelial cell prostaglandin (PG) production by hormones, vasoactive drugs, and inflammatory mediators in an environment that can be tightly controlled and that is unaffected by interactions with other cell types, physical stimulation, or alterations in oxygenation. The most potent stimuli for RCME cell PG secretion were substances associated with inflammation, including histamine, interleukin 1, leukotriene D4, fMet-Leu-Phe, interferon-gamma, and exogenous phospholipases. Inhibition of calcium availability by lower [Ca2+]o or by treatment with calcium channel blockers reduced A23187-stimulated PG release but increased PG synthesis from exogenous arachidonic acid (AA). These observations suggest that Ca2+ may regulate several steps in the pathway leading to PG synthesis and release. Elevated intracellular [Ca2+] may, on the one hand, promote PG production by stimulating phospholipase A2 leading to AA release and, on the other hand, limit the magnitude of the response by increasing the rate of AA reacylation. Glucocorticoids reduce PG production by RCME cells via an action that requires new protein and mRNA synthesis and appears to involve the production of an endothelial cell-derived phospholipase inhibitory protein, or "endocortin." Thus, microvascular endothelial cells can both contribute to (by the release of PGs and possibly platelet-activating factor-acether) and limit (by the production of endocortins) the degree of a local inflammatory response in the heart.     

The Fine Structure of Some Blood Vessels of the Earthworm, Eisenia foetida

The fine structure of the main dorsal and ventral circulatory trunks and of the subneural vessels and capillaries of the ventral nerve cord of the earthworm, Eisenia foetida, has been studied with the electron microscope. All of these vessels are lined internally by a continuous extracellular basement membrane varying in thickness (0.03 to 1 µ) with the vessel involved. The dorsal, ventral, and subneural vessels display inside this membrane scattered flattened macrophagic or leucocytic cells called amebocytes. These lie against the inner lining of the basement membrane, covering only a small fraction of its surface. They have long, attenuated branching cell processes. All of these vessels are lined with a continuous layer of unfenestrated endothelial cells displaying myofilaments and hence qualifying for the designation of "myoendothelial cells." The degree of muscular specialization varies over a spectrum, however, ranging from a delicate endowment of thin myofilaments in the capillary myoendothelial cells to highly specialized myoendothelial cells in the main pulsating dorsal blood trunk, which serves as the worm's "heart" or propulsive "aorta." The myoendothelial cells most specialized for contraction display well organized sarcoplasmic reticulum and myofibrils with thick and thin myofilaments resembling those of the earthworm body wall musculature. In the ventral circulatory trunk, circular and longitudinal myofilaments are found in each myoendothelial cell. In the dorsal trunk, the lining myoendothelial cells contain longitudinal myofilaments. Outside these cells are circular muscle cells. The lateral parts of the dorsal vessels have an additional outer longitudinal muscle layer. The blood plasma inside all of the vessels shows scattered particles representing the circulating earthworm blood pigment, erythrocruorin.