Renin expression in large renal vessels during fetal development depends on functional beta1/beta2-adrenergic receptors

During nephrogenesis, renin expression shifts from large renal arteries toward smaller vessels in a defined spatiotemporal pattern, finally becoming restricted to the juxtaglomerular position. Chronic stimulation in adult kidneys leads to a recruitment of renin expression in the upstream vasculature. The mechanisms that control this characteristic switch-on and switch-off in the immature and adult kidney are not well-understood. Previous studies in mice with juxtaglomerular cell-specific deletion of the adenylyl cyclase-stimulatory G protein Gsα suggested that signaling along the cAMP pathway plays an essential role for renin expression during nephrogenesis and in the adult kidney. To identify the Gsα-dependent receptor that might be involved in activating this pathway, the present studies were performed to compare renin expression in wild types with that in mice with targeted deletions of β(1) and β(2)-adrenoceptors. The sympathetic nervous system is an important regulator of the renin system in the adult kidney so that activation of β-adrenenoceptors may also participate in the activation of renin expression along the developing arterial tree and in upstream vasculature in adulthood. Compared with wild-types, renin expression was found to be significantly lower at all developmental stages in the kidneys of β(1)/β(2) Adr(-/-) mice. Three-dimensional analysis showed reduced renin expression in all segments of the vascular tree in mutants and a virtual absence of renin expression in the large arcuate arteries. Adult mutant kidneys showed the typical upstream renin expression after chronic stimulation. Tyrosine hydroxylase staining in fetal and postnatal kidneys revealed that sympathetic innervation of renin-producing cells occurs early in fetal development. Our data indicate that genetic disruption of β-adrenergic receptors reduces basal renin expression along the developing preglomerular tree and in adult kidneys. Furthermore, β-adrenergic receptor input is critical for the expression of renin in large renal vessels during early fetal development.     

Arterial vascularization of the tail of the pancreas with special reference to the relation of the tail and body vessels

The cauda pancreatis has a characteristic pattern of vascularization. Among the big arterial stems surrounding it, up to 4 arteries, 'caudal arteries', nourish the arterial system of the cauda. These stems originate especially in the Arteria gastroepiploica sinistra and in the lower main splenic branch of the Arteria lienalis. The vascular relations between corpus and cauda can be of different kinds. Five basic types of relations can be identified: type I: the cauda is supplied exclusively by caudal arteries; type II: at least one caudal artery anastomoses with the vessels of the corpus; type III: the cauda is supplied both by the caudal arteries and by vessels of the corpus (non-anastomosing); type IV: combined forms of blood supply by caudal arteries and corpus arteries by way of anastomoses and non-anastomosing vessels are found; type V: the cauda is supplied exclusively be vessels stemming from the corpus. In each of these five types, individual vessels supplying the cauda can assume the function of a terminal vessel.     

Arterial identity of endothelial cells is controlled by local cues.

The ephrins and their Eph receptors comprise the largest family of receptor tyrosine kinases. Studies on mice have revealed an important function of ephrin-B2 and Eph-B4 for the development of the arterial and venous vasculature, respectively, but the mechanisms regulating their expression have not been studied yet. We have cloned a chick ephrin-B2 cDNA probe. Expression was observed in endothelial cells of extra- and intraembryonic arteries and arterioles in all embryos studied from day 2 (stage 10 HH, before perfusion of the vessels) to day 16. Additionally, expression was found in the somites and neural tube in early stages, and later also in the smooth muscle cells of the aorta, parts of the Müllerian duct, dosal neural tube, and joints of the limbs. We isolated endothelial cells from the internal carotid artery and the vena cava of 14-day-old quail embryos and grafted them separately into day-3 chick embryos. Reincubation was performed until day 6 and the quail endothelial cells were identified with the QH1 antibody. The grafted arterial and venous endothelial cells expressed ephrin-B2 when they integrated into the lining of arteries. Cells that were not integrated into vessels, or into vessels other than arteries, were ephrin-B2-negative. The studies show that the expression of the arterial marker ephrin-B2 is controlled by local cues in arterial vessels of older embryos. Physical forces or the media smooth muscle cells may be involved in this process.     

Arterial adaptations to altered blood flow

Arterial remodeling in response to altered blood flow is believed to be critical to vascular adaptations to developmental, physiological, pathological, and therapeutically induced changes in blood flow. To assess this remodeling, we used left-to-right carotid anastomosis to increase blood flow in the right common carotid arteries of adult rabbits by 60%. After 2 months, these vessels exhibited no compensatory enlargement. In contrast, the same procedure performed in 5- to 6-week-old weanling rabbits resulted in accelerated growth of the vessels: diameters exceeded those of control arteries by 19% after 2 months. Common carotid arteries in adult rabbits remodeled to produce a diameter reduced by 23% when blood flow was reduced by 63% by external carotid ligation. This adaptation restored shear stress exerted on the vessel wall to control levels. The reduced diameter was not reversed when the vessels were maximally dilated with nitroprusside, adenosine, and forskolin; however, normal diameters were restored within 1 week when normal blood flows were reestablished. Thus, the adult arteries did not respond to increased blood flow produced by the anastomosis, but this procedure did reverse adaptations to decreased flow. In contrast, immature arteries were responsive to this increase in blood flow, even in the absence of prior flow modulation.     

Contribution of epoxyeicosatrienoic acids to flow-induced dilation in arteries of male ERalpha knockout mice: role of aromatase

We studied the roles of estrogen receptors (ER) and aromatase in the mediation of flow-induced dilation (FID) in isolated arteries of male ERalpha-knockout (ERalpha-KO) and wild-type (WT) mice. FID was comparable between gracilis arteries of WT and ERalpha-KO mice. In WT arteries, inhibition of NO and prostaglandins eliminated FID. In ERalpha-KO arteries, N(omega)-nitro-L-arginine methyl ester (L-NAME) inhibited FID by approximately 26%, whereas indomethacin inhibited dilations by approximately 50%. The remaining portion of the dilation was abolished by additional administration of 6-(2-proparglyoxyphenyl)hexanoic acid (PPOH) or iberiotoxin, inhibitors of epoxyeicosatrienoic acid (EET) synthesis and large-conductance potassium channels, respectively. By using an electrophysiological technique, we found that, in the presence of 10 dyne/cm(2) shear stress, perfusate passing through donor vessels isolated from gracilis muscle of ERalpha-KO mice subjected to L-NAME and indomethacin elicited smooth muscle hyperpolarization and a dilator response of endothelium-denuded detector vessels. These responses were prevented by the presence of iberiotoxin in detector or PPOH in donor vessels. Gas chromatography-mass spectrometry (GC-MS) analysis indicated a significant increase in arterial production of EETs in ERalpha-KO compared with WT mice. Western blot analysis showed a significantly reduced endothelial nitric oxide synthase expression but enhanced expressions of aromatase and ERbeta in ERalpha-KO arteries. Treatment of ERalpha-KO arteries with specific aromatase short-interfering RNA for 72 h, knocked down the aromatase mRNA and protein associated with elimination of EET-mediation of FID. Thus, FID in male ERalpha-KO arteries is maintained via an endothelium-derived hyperpolarizing factor/EET-mediated mechanism compensating for reduced NO mediation due, at least in part, to estrogen aromatized from testosterone.     

Thalamic arterial pattern: an endocast and scanning electron microscopic study in normotensive male rats

Rat cerebral vasculature serves as a model for study of the pathophysiology of stroke in humans. Human thalamic arteries show a high incidence of stroke. The objective is to describe the thalamic arterial vascular pattern in normotensive male rats as the initial step for quantitative histochemical studies of enzyme activities in the walls of these vessels. Intracardiac injections of methyl methacrylate monomer provide detailed vascular endocasts. The thalamic vascular bed defined by in situ dissection, serial reconstruction, and light and scanning electron microscopy of endocasts contained four groups of vessel: ventral medial thalamic arteries, thalamic branches from the posterior cerebral artery, and ventral lateral and ventral anterior thalamic arteries. Thalamic vessels are muscular arterioles that, after three to four bipinnate branches, feed into a continuous capillary bed (no loops). The parent vessels and their subsequent branches have been evaluated in terms of their mean internal diameters, mean interbranch intervals, and branch angles. The arterial patterns to rat and human thalami are very similar, with the exception of the anterior choroidal artery which is missing in the rat. The branches supplying the thalamus in both the rat and human are closely associated with the circle of Willis; however, the constituent parts of the circle in rat vary from the pattern in human brain. The rat thalamic arteries show morphological features similar to those seen in the stroke-prone ganglionic arteries in the human basal ganglia.     

Defining the Role of Vascular Smooth Muscle Cell Apoptosis in Atherosclerosis

Vascular smooth muscle cell (VSMC) apoptosis occurs in many arterial diseases, including aneurysm formation, angioplasty restenosis and atherosclerosis. Although VSMC apoptosis promotes vessel remodelling, coagulation and inflammation, its precise contribution to these diseases is unknown, given that apoptosis frequently accompanies vessel injury or alterations to flow. Using transgenic mice with selective induction of VSMC apoptosis, a recent study has precisely determined the direct consequences of VSMC apoptosis in both normal vessels and atherosclerotic plaques. Surprisingly, normal arteries can withstand huge cell losses with little change in active or passive properties. Normal vessels demonstrate highly efficient clearance of apoptotic bodies, even in the absence of professional phagocytes. In contrast, VSMC apoptosis alone is sufficient to induce multiple features of vulnerability to rupture in plaques, identifying VSMC apoptosis as a critical process determining plaque stability.     

The vasculature of the rat embryo: an electron microscope study

The ultrastructure of portions of the arterial and venous systems of the 11.5 day old Wistar rat embryos has been studied by scanning and transmission electron microscopy. The vessels at this stage of development are in the form of capillaries, and the arterial and venous types can be distinguished by the morphology of the endothelial cells by SEM. The endothelial cells of the arterial vessels gave prominent nuclear bulges and numerous microvilli apart from their spindle shape, whilst those of the veins appear flattened, are polygonal in shape, and have few microvilli. Transmission electron microscopy shows that the endothelial cells of the arteries and veins are identical in structure. The ultrastructure of these cells resembles that of endothelial cells at later stages of development including the adult type in that mature forms of cytoplasmic organelles are obtained. In studies on the intercellular junctions and fenestrations with lanthanum nitrate, the impression is formed that the vessels at this stage are impermeable to small molecular size particles, compared with adult capillaries. This suggests that cytoplasmic vesicles must play a major role in the transport of macromolecules in the 11.5 day embryonic vessels.     

Development of the hemochorial maternal vascular spaces in the placenta through endothelial and vasculogenic mimicry

The maternal vasculature within the placenta in primates and rodents is unique because it is lined by fetal cells of the trophoblast lineage and not by maternal endothelial cells. In addition to trophoblast cells that invade the uterine spiral arteries that bring blood into the placenta, other trophoblast subtypes sit at different levels of the vascular space. In mice, at least five distinct subtypes of trophoblast cells have been identified which engage maternal endothelial cells on the arterial and venous frontiers of the placenta, but which also form the channel-like spaces within it through a process analogous to formation of blood vessels (vasculogenic mimicry). These cells are all large, post-mitotic trophoblast giant cells. In addition to assuming endothelial cell-like characteristics (endothelial mimicry), they produce dozens of different hormones that are thought to regulate local and systemic maternal adaptations to pregnancy. Recent work has identified distinct molecular pathways in mice that regulate the morphogenesis of trophoblast cells on the arterial and venous sides of the vascular circuit that may be analogous to specification of arterial and venous endothelial cells.     

Vessel tortuousity and reduced vascularization in the fetoplacental arterial tree after maternal exposure to polycyclic aromatic hydrocarbons

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants and the main toxicants found in cigarettes. Women are often exposed to PAHs before pregnancy, typically via prepregnancy smoking. To determine how prepregnancy exposure affects the fetoplacental vasculature of the placenta, we exposed female mice to PAHs before conception, perfused the fetoplacental arterial trees with X-ray contrast agent, and imaged the vasculature ex vivo by microcomputed tomography (micro-CT) at embryonic day 15.5. Automated vascular segmentation and flow calculations revealed that in control trees, <40 chorionic plate vessels (diameter>180 μm) gave rise to ～1,300 intraplacental arteries (50-180 μm), predicting an arterial vascular resistance of 0.37±0.04 mmHg·s·μl(-1). PAH exposure increased vessel curvature of chorionic plate vessels and significantly increased the tortuousity ratio of the tree. Intraplacental arteries were reduced by 17%, primarily due to a 27% decrease in the number of arteriole-sized (50-100 μm) vessels. There were no changes in the number of chorionic vessels, the depth or span of the tree, the diameter scaling coefficient, or the segment length-to-diameter ratio. PAH exposure resulted in a tree with a similar size and dichotomous branching structure, but one that was comparatively sparse so that arterial vascular resistance was increased by 30%. Assuming the same pressure gradient, blood flow would be 19% lower. Low flow may contribute to the 23% reduction observed in fetal weight. New insights into the specific effects of PAH exposure on a developing arterial tree were achieved using micro-CT imaging and automated vascular segmentation analysis.     

Choose your fate: artery, vein or lymphatic vessel?

The specification of cell fate is integral to embryonic development. Recent research has identified several molecules that are involved in the development of the embryonic vasculature. Their combined actions are required for the specification and development of the arteries, veins and lymphatic vessels; vascular networks that are vital for embryonic and adult survival, and whose malfunction causes major pathological disorders. Recent discoveries have impacted our understanding of the embryonic origins of arterial, venous and lymphatic endothelial cells and the signals that mediate their navigation into mature, functional circulatory systems.     

Gross anatomy of the arterial supply of the stomach of the North American beaver (Castor canadensis).

The arterial pattern of the stomach of the North American beaver is studied by dissection of height specimens. The arrangement of the arteries resembles the typical mammalian pattern, although some variations are described. For example, the celiac artery gives off two large vessels, the cardiac and fundic arteries, which supply the corresponding regions of the stomach. Also, the right gastric artery originates from the gastroduodenal vessel instead of the hepatic artery.     

Bifurcation asymmetry of the porcine coronary vasculature and its implications on coronary flow heterogeneity

The branching pattern of the coronary arteries and veins is asymmetric, i.e., many small vessels branch off of a large trunk such that the two daughter vessels at a bifurcation are of unequal diameters and lengths. One important implication of the geometric vascular asymmetry is the dispersion of blood flow at a bifurcation, which leads to large spatial heterogeneity of myocardial blood flow. To document the asymmetric branching pattern of the coronary vessels, we computed an asymmetry ratio for the diameters and lengths of all vessels, defined as the ratio of the daughter diameters and lengths, respectively. Previous data from silicone elastomer cast of the entire coronary vasculature including arteries, arterioles, venules, and veins were analyzed. Data on smaller vessels were obtained from histological specimens by optical sectioning, whereas data on larger vessels were obtained from vascular casts. Asymmetry ratios for vascular areas, volumes, resistances, and flows of the various daughter vessels were computed from the asymmetry ratios of diameters and lengths for every order of mother vessel. The results show that the largest orders of arterial and venous vessels are most asymmetric and the degree of asymmetry decreases toward the smaller vessels. Furthermore, the diameter asymmetry at a bifurcation is significantly larger for the coronary veins (1.7-6.8 for sinus veins) than the corresponding arteries (1.5-5.8 for left anterior descending coronary artery) for orders 2-10, respectively. The reported diameter asymmetry at a bifurcation leads to significant heterogeneity of blood flow at a bifurcation. Hence, the present data quantify the dispersion of blood flow at a bifurcation and are essential for understanding flow heterogeneity in the coronary circulation.     

Estrogen induces vascular wall dilation: mediation through kinase signaling to nitric oxide and estrogen receptors alpha and beta

Estrogen has been shown to affect vascular cell and arterial function in vitro and in vivo. Here we examined the ability of estradiol (E(2)) to cause rapid arterial dilation of elastic and muscular arteries in vivo and the mechanisms involved. E(2) administration caused a rapid increase in the outer wall diameter of both types of arteries in ovariectomized female mice. This resulted from estrogen receptor (ER)-mediated stimulation of nitric oxide production, demonstrated by preinjecting the mice arteries with a soluble inhibitor of nitric oxide (monomethyl l-arginine) and by showing the absence of E(2) action in eNOS-/- mice. Rapid activation of both ERK/MAP kinase and phosphatidylinositol 3-kinase activity was found in the E(2)-exposed arteries, and inhibiting either kinase prevented the vasodilatory action of E(2). Kinase activation and vasodilator responses to E(2) were absent in either ERalpha or ERbeta knock-out mice, implicating both receptor subtypes as mediating this E(2) action. These results indicate that E(2) modulation of arterial tonus through plasma membrane ER and rapid signaling could underlie many previously observed actions of estrogen reported to occur in women.     

Receptor protein tyrosine phosphatase mu expression as a marker for endothelial cell heterogeneity; analysis of RPTPmu gene expression using LacZ knock-in mice

The receptor-like protein tyrosine phosphatase mu (RPTPmu) belongs to the subfamily of meprin, A5, RPTPmu (MAM) domain-containing RPTPs, which are thought to play an important role in cell-cell adhesion mediated processes. The current study was designed to examine the expression pattern of RPTPmu in mice. We have generated RPTPmu-LacZ knock-in mice that express the beta-galactosidase (LacZ) reporter gene under the control of the RPTPmu promoter. LacZ expression patterns were analysed in embryos and adult mice by whole mount LacZ staining. Analysis of beta-galactosidase activity of heterozygous embryos and adult tissues revealed RPTPmu expression in endothelial cells of arteries and capillaries. In contrast, expression was virtually absent in endothelial cells of veins and in fenestrated endothelial cells in the adult liver and spleen. Moreover, RPTPmu expression was found in endothelial cells from the endocardium and the aorta in embryos, but not in adult mice. In addition to heterogeneous expression in endothelial cells, RPTPmu expression was found in cardiac muscle cells but not in skeletal muscle cells or smooth muscle cells. Expression was also found in Type II pneumonocytes in the lung alveoli and in Purkinje cells and other neurons in the brain. The specific expression of RPTPmu in arterial endothelial cells and in cardiac myocytes suggests that RPTPmu may play a role in the regulation of cardiovascular functions.     

Three-dimensional analysis of the arterial pattern of the upper limbs in Lorisiformes (Prosimiae, Primates)

A study of the arterial patterns of the upper limbs in Lorisiformes (Prosimiae), especially those of the rete mirabile and their correlating arteries, was carried out by three-dimensional arteriographic analysis. The rete displayed at least two types of plexiform distribution: (1) a vascular bundle in Lorisidae, which consists of a division of the main artery into a principal trunk surrounded upwards by about 50 small arteries, and (2) a simple network pattern in Galagidae, which, at most, is composed of simple vascular networks of the nature of a few widely scattered anastomoses. The arterial patterns of the upper limb in Lorisiformes are basically the same, but the position of divergence and the number and size of the vessels in the rete differ. The arterial patterns of the upper limbs in Lorisiformes closely resemble the development of the vessels in the 21- to 23-mm stages of human embryonic growth. In this study, we observed some similarity in the patterns between the rete mirabile and the superficial brachial artery in man.     

Increased sympathetic innervation in the cerebral and mesenteric arteries of hypertensive rats

The density of catecholamine-containing nerve fibers was studied in the cerebral and mesenteric arteries from normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and stroke-prone SHR (SHRSP) in the growing (SHR, WKY) and adult (SHR, SHRSP, WKY) animals. Cerebral arteries from SHR showed an increased adrenergic innervation from day 1. The nerve plexuses reached an adult pattern earlier in SHR than in WKY. The arteries from adult SHR and SHRSP (22 weeks old) showed a markedly higher nerve density than WKY. There was a positive linear correlation between blood pressure and nerve density for four cerebral arteries. The mesenteric arteries were not innervated at birth. However, hyperinnervation of these arteries in the SHR was already present at 10 days of age as compared with WKY. Sympathectomy with anti-nerve growth factor and guanethidine caused a complete disappearance of fluorescent fibers in the mesenteric arteries from SHR and WKY, and in the cerebral arteries of WKY. The same procedure caused only partial denervation of the cerebral arteries from hypertensive animals. We postulate that the increase in nerve density in the cerebral arteries from the hypertensive rats may contribute to the development of arterial hypertrophy in chronic hypertension through the trophic effect of the sympathetic innervation on vascular structure.     

Assessment of endothelial function of large, medium, and small vessels: a unified myograph

Endothelial dysfunction precedes the development of morphological atherosclerotic changes and can also contribute to lesion development in cardiovascular diseases. Currently, there is a lack of a single method to determine endothelial function of the entire range of vessel dimensions from aorta to arterioles. Here we assessed endothelial function of a large range of size arteries using a unified isovolumic myograph method. The method maintains a constant volume of fluid in the lumen of the vessel during contraction and relaxation, which are characterized by an increase and a decrease of pressure, respectively. Segments of six aortas, six common femoral arteries, and six mesenteric arteries from rats; six carotid arteries from mice; and six coronary and carotid arteries from pigs were used. The endothelium-dependent dose-response vasorelaxation was determined with endothelium-dependent vasodilators while arterial preconstriction was induced with vasoconstrictors at a submaximal dose. The circumferential midtension during vascular reactivity varied from 43.1 ± 7.9 to 2.59 ± 0.46 mN/mm (from large to small arteries), whereas the circumferential midstress showed a much smaller variation from 217 ± 23.5 to 123 ± 15.3 kPa (in the same range of vessels). We also found that overinflation and axial overelongation compromised endothelium-dependent vasorelaxation to underscore the significance of vessel preload. In conclusion, an isovolumic myograph was used to unify arterial vasoreactivity from large to small arteries and shows the uniformity of wall stress and %tension throughout the range of vessel sizes.     

Branchial vascular pathways in two species of Tetraodontiformes and the concept of secondary vessels and nutrient arteries

The vascular organisation of the branchial basket was examined in two Tetraodontiform fishes; the three-barred porcupinefish, Dicotylichthys punctulatus and the banded toadfish, Marylina pleurosticta by scanning electron microscopy of vascular casts and standard histological approaches. In D. punctulatus, interarterial anastomoses (iaas) originated at high densities from the efferent filamental and branchial arteries, subsequently re-anastomosing to form progressively larger secondary vessels. Small branches of this system entered the filament body, where it was interspersed between the intrafilamental vessels. Large-bore secondary vessels ran parallel with the efferent branchial arteries, and were found to constitute an additional arterio–arterial pathway, in that these vessels exited the branchial basket in company with the mandibular, the carotid and the afferent and efferent branchial arteries, from where they gave rise to capillary beds after exit. Secondary vessels were not found to supply filament muscle; rather these tissues were supplied by single specialised vessels running in parallel between the efferent and afferent branchial arteries in both species examined. Although the branchial vascular anatomy was generally fairly similar for the two species examined, iaas were not found to originate from any branchial component in the banded toadfish, M. pleurosticta, which instead showed a moderate frequency of iaas on other vessels in the cephalic region. It is proposed that four independent vascular pathways may be present within the teleostean gill filament, the conventional arterio–arterial pathway across the respiratory lamellae; an arterio–arterial system of secondary vessels supplying the filament and non-branchial tissues; a system of vessels supplying the filament musculature; and the intrafilamental vessels (central venous sinus). The present study demonstrates that phylogenetic differences in the arrangement of the branchial vascular system occur between species of the same taxon.     

Comparison of cerebral base arteries in antelopes of Tragelaphus,Taurotragus and Boselaphus genera

Studies were conducted on preparations of head arteries, including cerebral base arteries of sitatunga (n = 14), nyala n = 16) and Greater kudu n = 4) of Tragelaphus genus, Common eland n = 7) from the tribe of Tragelaphini and the largest Asiatic Nilgai antelope n = 9) from Boselaphini tribe. Blood vessels of the cerebral arterial circle in studied antelopes were found to arise from terminal division of intracranial segments of internal carotid arteries, which emerge from the pairwise rostral epidural rete mirabile. Due to obliteration of the extracranial segment of internal carotid artery, the cerebral arterial circle of studied antelopes is supplied with blood mainly through maxillary artery, with mediation of blood vessels of rostral epidural rete mirabile. The system of cerebral base arteries in selected representatives of Tragelaphus, Taurotragus and Boselaphus, in contrast to other species of Bovinae subfamily, manifests the absence of caudal epidural rete mirabile. The pattern of cerebral base arteries in studied antelopes is consistent with position of the species in taxonomy worked out by Simpson (Bull Am Mus Nat Hist 85:1–350, 1945) and McKenna and Bell (Classification of mammals above the species level. Columbia University Press, New York, pp I–XII, 1997).