Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology.

Blood vessels form one of the body's largest surfaces, serving as a critical interface between the circulation and the different organ environments. They thereby exert gatekeeper functions on tissue homeostasis and adaptation to pathologic challenge. Vascular control of the tissue microenvironment is indispensable in development, hemostasis, inflammation, and metabolism, as well as in cancer and metastasis. This multitude of vascular functions is mediated by organ-specifically differentiated endothelial cells (ECs), whose cellular and molecular heterogeneity has long been recognized. Yet distinct organotypic functional attributes and the molecular mechanisms controlling EC differentiation and vascular bed-specific functions have only become known in recent years. Considering the involvement of vascular dysfunction in numerous chronic and life-threatening diseases, a better molecular understanding of organotypic vasculatures may pave the way toward novel angiotargeted treatments to cure hitherto intractable diseases. This Review summarizes recent progress in the understanding of organotypic vascular differentiation and function.

Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy.

Anti-VEGF-based antiangiogenic drugs are designed to block tumor angiogenesis for treatment of cancer patients. However, anti-VEGF drugs produce off-tumor target effects on multiple tissues and organs and cause broad adverse effects. Here, we show that vasculatures in endocrine organs were more sensitive to anti-VEGF treatment than tumor vasculatures. In thyroid, adrenal glands, and pancreatic islets, systemic treatment with low doses of an anti-VEGF neutralizing antibody caused marked vascular regression, whereas tumor vessels remained unaffected. Additionally, a low dose of VEGF blockade significantly inhibited the formation of thyroid vascular fenestrae, leaving tumor vascular structures unchanged. Along with vascular structural changes, the low dose of VEGF blockade inhibited vascular perfusion and permeability in thyroid, but not in tumors. Prolonged treatment with the low-dose VEGF blockade caused hypertension and significantly decreased circulating levels of thyroid hormone free-T3 and -T4, leading to functional impairment of thyroid. These findings show that the fenestrated microvasculatures in endocrine organs are more sensitive than tumor vasculatures in response to systemic anti-VEGF drugs. Thus, our data support the notion that clinically nonbeneficial treatments with anti-VEGF drugs could potentially cause adverse effects.

[EFFICACY OF WELDING TECHNOLOGY AS A PRINCIPAL METHOD OF DISSECTION AND HEMOSTASIS IN ENDOCRINAL SURGERY].

Today in the clinic all surgical interventions on endocrinal organs are conducted, using welding technology. Comparative analysis of the operative interventions efficacy, performed applying a standard method (control group) and using welding technology (the main group), was conducted. Performance of operations, using electric welding technologies have permitted to reduce the operative intervention duration by 20 - 30%, the blood loss volume--by 30 - 50%, a postoperative pain syndrome severity and the analgetics expense--by 20%, a postoperative stationary treatment duration--by 1-2 days.

The regulation of circulating ghrelin - with recent updates from cell-based assays.

Ghrelin is a stomach-derived orexigenic hormone with a wide range of physiological functions. Elucidation of the regulation of the circulating ghrelin level would lead to a better understanding of appetite control in body energy homeostasis. Earlier studies revealed that circulating ghrelin levels are under the control of both acute and chronic energy status: at the acute scale, ghrelin levels are increased by fasting and decreased by feeding, whereas at the chronic scale, they are high in obese subjects and low in lean subjects. Subsequent studies revealed that nutrients, hormones, or neural activities can influence circulating ghrelin levels in vivo. Recently developed in vitro assay systems for ghrelin secretion can assess whether and how individual factors affect ghrelin secretion from cells. In this review, on the basis of numerous human, animal, and cell-based studies, we summarize current knowledge on the regulation of circulating ghrelin levels and enumerate the factors that influence ghrelin levels.

Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features.

Angiogenesis, a process related to tumor growth and malignancy, is stimulated by several growth factors. Among these is vascular endothelial growth factor (VEGF), which acts on endothelial cells by binding with 2 specific receptors, VEGFR1 and VEGFR2. Recent studies have demonstrated that VEGF expression is correlated with microvessel density (MVD) and tumor progression. Digestive endocrine tumors are heterogeneous neoplasms exhibiting variable biological aggressiveness and behavior that often are not predictable on morphologic grounds alone. The aims of this study were to evaluate the expression of VEGF, VEGFR1, and VEGFR2 in digestive endocrine tumors and to examine its correlation with MVD and malignancy. A total of 84 specimens from endocrine neoplasms and normal gut and pancreatic tissue were immunohistochemically studied using specific antibodies directed against VEGF, VEGFR1, VEGFR2, endothelial antigens, and gastroenteropancreatic hormones. Ultrastructural immunocytochemistry was performed to identify the cellular localization of VEGF and the VEGFRs. In normal tissues, VEGF immunoreactivity was detected in G cells and PP cells. Ultrastructurally, VEGF was localized within secretory granules. The VEGFRs were not significantly expressed by normal endocrine cells. VEGF-immunoreactive (IR) cells were detected in 40 of 83 tumors, mainly G cell and enterochromaffin cell neoplasms. VEGFR1-IR cells were found in 44 of 82 tumors, and VEGFR2-IR cells were found in 55 of 82 tumors, with no predilection for any specific tumor type. The expression of VEGF and its receptors did not correlate with MVD or malignancy. These results suggest that in normal tissues, endothelial functions may be regulated by VEGF produced by some endocrine cells and that a VEGF/VEGFR binding mechanism may be involved in tumorigenesis, but not in tumor progression and aggressiveness.

Angiogenesis in endocrine glands: special reference to the expression of vascular endothelial growth factor.

Recent studies have shown that several angiogenic growth factors are produced and secreted by normal endocrine cells and are increased in pathological states of endocrine glands, including inflammation, hyperplasia, and neoplasia. Expression of corresponding receptors on epithelial cells and/or endothelial cells enables these angiogenic factors to influence growth and function of the endocrine tissues by auto- or paracrine mechanisms. Some of the angiogenic factors are also considered to be involved in angiogenesis, which is a critical process in tumor formation and progression. Vascular endothelial growth factor (VEGF) is regarded as one of most important angiogenic factors with specific effects on endothelial cell growth and vascular permeability, and is isolated from a variety of normal and neoplastic endocrine cells. In this article, recent studies on angiogenic factors, especially on expression of VEGF, are reviewed in the field of endocrine systems.

Microvascularization of corpuscles of Stannius in teleost fishes.

Blood supply and microvascular patterns of Stannius corpuscles were studied by scanning electron microscopy of vascular corrosion casts in the teleost fishes Blennius pavo, Zosterisessor ophiocephalus, and Gasterosteus aculeatus. Microvascular casts demonstrated that Stannius corpuscles--depending on their location--have an arterial supply derived either directly from the dorsal aorta, from the trunk of the first ventral segmental artery of the tail, or from a renal artery. Supplying arteries form a capsular capillary bed and a parenchymal capillary bed; both are composed of fine, freely anastomosing vessels with a homogeneous isotropic distribution. Central venules arise deep in the corpuscles. In the capsule, they form a single vein which drains into a segmental vein or directly into the caudal vein. Stanniocalcin, the hormone of the Stannius corpuscle, enters the renal circulation and reaches its main target organs, the gills, via posterior cardinal veins--heart--ventral aorta. Occasionally, some capsular venules empty into the trunk kidney peritubular venules. Capillaries are fenestrated and are embraced by pericytes with long, slender processes. The perivascular space contains collagen fibrils. Nerve fibers are found close to endothelial cells and pericytes. Vascular patterns of Stannius corpuscles are compared with those of the rat parathyroid glands and are discussed in respect to physiological implications.

Structure of the corpuscles of Stannius in the euryhaline teleost Takifugu niphobles (Tetraodontiformes, Teleostei), with special regard to vascularization and extravascular channel system.

Vascularization and the extravascular channel system of the corpuscles of Stannius in a euryhaline teleost, Takifugu niphobles, were studied by scanning electron microscopy of the vascular corrosion cast, and histochemistry of exogenously injected horseradish peroxidase as a macromolecular tracer. The corpuscles were apposed to the caudal part of the ureter, away from the mesonephric kidney, and were supplied with arterioles from the genital artery running ventrally as a ramus of the dorsal aorta. Elaborate capillary networks irrigating the glandular lobules were collected by the venules to drain into the posterior cardinal veins. Electron microscopic examination of the glands demonstrated two types of secretory cells, type-1 cells with large granules, and type-2 cells with smaller granules. The type-1 cells, predominating in the gland, occasionally showed exocytosis of the secretory granules, mainly into intercellular spaces between adjoining cells. Exocytosis was also evident in the type-2 cells. The tracer molecule injected was visualized histochemically within the capillary lumina and intercellular spaces throughout the gland. The labelled spaces intercommunicated with each other to form an extensive extravascular channel system as a diffusing pathway within the gland. The possible role of this system in hormone transport and/or storage was discussed.

Circulatory effects of a depilatory dose of mouse epidermal growth factor in sheep.

1. Haemodynamic parameters and tissue blood flow rates were measured in two groups of five sheep infused I.V. for 24 h with either saline or 128.6 micrograms mouse epidermal growth factor (mEGF) kg-1 body weight. Measurements were made preinfusion and at +3, +12, +24, +27 and +48 h. We wished to assess relationships between blood flow rates and known functional changes in various organs during EGF treatment, especially any relationship between skin blood flow rate and the known depilatory effects of the protein in sheep. 2. Cardiac output increased and total peripheral resistance and mean arterial pressure decreased during and after infusion in the mEGF-treated group relative to the control group. 3. The greatest increase in blood flow rates occurred in woolled skin (+500%) during mEGF infusion, a result which in itself may have been disparate with the known depilatory effects of EGF. The mucosas of the alimentary tract (except abomasum) and the submaxillary and sublingual salivary glands also showed vasodilatation. 4. There were short-term increases in pituitary and adrenal gland blood flow that may have been associated with the corticotrophin-releasing factor properties of EGF. Flow in the thyroids showed the greatest increase post-infusion when thyroid hormone metabolism may have been reverting to normal. Blood flow rates decreased in the pancreas and perirenal fat. 5. Our general conclusion was that mEGF had specific vasodilator effects in the skin, the thyroid, submaxillary and sublingual glands and the mucosas of most of the alimentary tract.

Effect of fasting on capillary blood flow in sheep.

Capillary blood flow rate was measured in 29 tissues in two hourly fed and 26 hour fasted Blackface and Clun lambs using the radiolabelled microsphere technique. Blood flow declined with fasting in alimentary tract, skin of the ear and some of the larger skeletal muscles. It was concluded that capillary perfusion in nerve tissue was not affected by fasting whereas tissues principally responsible for energy absorption, expenditure and retention can experience a fall in capillary blood flow during fasting.

A monomeric methyl and hydroxypropyl methacrylate injection medium and its utility in casting blood capillaries and liver bile canaliculi for scanning electron microscopy.

A mixture of 50-60% monomeric methyl methacrylate and 40-50% monomeric 2-hydroxypropyl methacrylate was supplemented with 1.5% benzoyl peroxide (catalyst) and 1.5% N,N-dimethylaniline (accelerator) and injected into glutaraldehyde-perfusion fixed rat hypophyseal and other endocrine organ blood vessels and biliary tracts. This injection medium rapidly polymerized at room temperature and did not require partial polymerization prior to injection. Good casts of blood vessels, including the hypophyseal capillaries, were obtained for scanning electron microscopy. The monomeric methacrylate medium possesses a great advantage over previous ones, as its fluidity enables the casting of very fine vessels such as bile canaliculi. In the case of non-fixed tissues, the monomeric methacrylate medium should be injected carefully, as it is toxic and destructive to the vessels.

Microvasculature as studied by the microvascular corrosion casting/scanning electron microscope method. I. Endocrine and digestive system.

This paper reviews firstly the microvascular corrosion casting/scanning electron microscope method and secondly the microvascular organization of endocrine and digestive system as revealed by this technique. Detailed descriptions of the microvascular arrangement of the hypophysis, pineal body, thyroid gland, pancreas, adrenal gland, salivary gland, liver, stomach and small intestine are given. Various hypotheses are also proposed regarding the physiological significance of the microcirculatory patterns observed.

[The effect of PEEP ventilation on hemodynamics and regional blood flow (author's transl)]. / Der Einfluss bon PEEP-Beatmung auf Gesamthämodynamik und regionale Organdurchblutung.

The beneficial effects of PEEP on lung function may be counteracted by its hemodynamic sequelae induced by a reduction of venous return due to the elevated intrathoracic pressure, and by an increased right ventricular afterload secondary to the rise of pulmonary vascular resistance. PEEP redistributes cardiac output in favor of brain, heart, adrenals and intestines, whereas the perfusion of stomach, pancreas and thyroid is diminished out of proportion to the fall of cardiac output. Total renal blood flow is relatively little affected; however, redistribution of intrarenal blood flow will result in a marked salt-water-retention. Reduction of hepatic artery flow, at higher levels of PEEP, may jeopardize liver tissue oxygenation. - Under clinical conditions, individual differences regarding preexisting cardiopulmonary and peripheral-vascular diseases may modify the PEEP-induced hemodynamic alterations in a wide range.

Blood flow distribution in dogs during hypothermia and posthypothermia.

Blood flow distribution in tissues of mongrel dogs during hypothermia was studied with radionuclide-tagged microspheres. The animals were cooled at 21 degrees C and rewarmed under thiamylal sodiuni anesthesia. During hypothermia, cardiac output fell to 20% of the control; the highest rate of blood flow relative to normothermic values was observed in the subendocardium of the left ventricle, and the lowest in the hypophysis. Each tissue showed specific reactions to hypothermia. During hypothermia the myocardial and brain-stem blood flows were about 40% of the control; almost all of the digestive tract, striated muscle, adrenal gland, and hypophysis blood flows were maintained at 20% or less of the control. After rewarming, cardiac output recovered to values significantly lower than control. The myocardium, brain, renal cortex, and striated and smooth muscle recovered to control levels; however, blood flow to the digestive organs, bronchial artery flow to the lung, and flow to the endocrine organs did not completely recover by 2 after rewarming.