Neoformation Of Blood Vessels Research Articles

COVID-19: effects on the lungs and heart

Neben der jährlich saisonal auftretenden Influenzaendemie stellt das sich pandemisch verbreitende SARS-CoV-2-Virus die weltweiten Gesundheitssysteme als vaskuläre Multiorganerkrankung COVID-19 vor ganz neue medizinische und sozioökonomische Herausforderungen. Bei beiden Viruserkrankungen kommt es insbesondere bei schweren Krankheitsverläufen zu einem fulminanten Lungenversagen, dem „acute respiratory distress syndrome“ (ARDS), welchem morphologisch meist ein unspezifischer diffuser Alveolarschaden mit hyalinen Membranen, Fibrinexsudaten und einem intraalveolären Ödem zugrunde liegt. Neben einer Infektion des Alveolarepithels und von Makrophagen durch das SARS-CoV-2-Virus scheint die COVID-19-Erkrankung zusätzlich durch eine vaskulozentrische Entzündungsreaktion mit Mikroangiopathie und aberranter Blutgefäßneubildung durch die sog. intussuszeptive Angiogenese charakterisiert zu sein. Zudem finden sich wahrscheinlich auf dem Boden dieser primär systemischen angiozentrischen Entzündung in vielen weiteren Organen, z. B. dem Herzen, im unterschiedlichen Ausmaß Gewebeschädigungen.

Nimotuzumab for Patients With Inoperable Cancer of the Head and Neck.

EGFR activation induces cell proliferation, neoformation of blood vessels, survival, and metastasis of the cancer cells. Nimotuzumab is an engineered, intermediate affinity anti-EGFR antibody, that apart from other drugs in its class, is very safe and does not cause hypomagnesemia or grade 3–4 cutaneous rash. The antibody inhibits cell proliferation and angiogenesis, activates natural killer cells, stimulates dendritic cell maturation, and induces cytotoxic T cells. Nimotuzumab restores MHC-I expression on tumor cells, hindering one of the EGFR immune-escape ways. The antibody has been extensively studied in 7 clinical trials, concurrently with irradiation or irradiation plus chemotherapy in subjects with inoperable head and neck tumors. Nimotuzumab was safe and efficacious in unfit patients receiving irradiation alone and in subjects treated with cisplatin and radiotherapy. In patients with locally advanced squamous cell carcinomas of the head and neck, nimotuzumab in combination with low dose cisplatin and radiotherapy was superior to cisplatin and radiotherapy in progression free survival, disease free survival, and locoregional tumor control.

ORAL MANIFESTATION OF CROHN DISEASE - A CASE REPORT

A 29-year-old male patient was referred to a specialized service with gingival lesions that lasted 10 years. The medical history showed untreated Crohn disease. Intraoral examination detected firm nodules at the vestibular retromolar region of the right and left mandibular molar, red in color, recovered by ulcerated mucosa, and both measuring 2 cm. The buccal mucosa revealed a swollen, cobllestone appearance and showed deep linear ulcerations. Incisional biopsy was performed, and histopathologic analysis showed a connective tissue with intense chronic inflammatory infiltrate and neutrophils, blood vessel neoformation, and epithelioid cells. We recommended the use of 0.12% topical chlorhexidine. Because of persistent oral lesions, the patient was redirected to a gastroenterologist for further investigations and systemic treatment. Clinical control remains for 2 months. Approximately one-third of Crohn disease patients develop extraintestinal manifestations. Treatment of oral lesions included treatment of the intestinal disease and cooperation between gastroenterologists and specialists in oral medicine.

Combined antibacterial/tissue regeneration response in thermal burns promoted by functional chitosan/silver nanocomposites

We report the combined antibacterial/tissue regeneration responses to thermal burns promoted by functional chitosan/silver nanocomposites (CS/nAg) with ultralow silver content (0.018wt.%, 7–30nm). Our approach allows one to produce CS/nAg nanocomposites without silver nanoparticles (nAg) agglomeration, with bactericide potency higher than 1wt.% of nAg (ca. 10nm) content and, promoting the healing process in controlled thermal burns. CS/nAg films exhibit high antibacterial activity against S. aureus and P. aeruginosa after 1.5h of incubation, demonstrating the bacterial penetration into hydrated films and their interaction with nAg. Additionally, exceptional healing of induced thermal burns was obtained by increasing myofibroblasts, collagen remodeling, and blood vessel neoformation. These factors are associated with epiderma regeneration after 7days of treatment with no nAg release. Our results corroborate the controlled synthesis of nAg embedded in CS matrix with combined antibacterial/biocompatibility properties aiming to produce functional nanocomposites with potential use in wound dressing and health care applications.

Looking for the Word "Angiogenesis" in the History of Health Sciences: From Ancient Times to the First Decades of the Twentieth Century.

This review deals with the origin of the term "angiogenesis", with an attention to John Hunter who is credited with this neologism. A part of the literature refers to a Hunter's work dating 1787, and the other part claims the first use of the term "angiogenesis" in the Hunter's masterpiece published in 1794. Since we were unable to find the term "angiogenesis" in Hunter's works, this review attempts to bring a new contribution to the historical research of this important concept, moving from ancient times to the first decades of the twentieth century, when "angiogenesis" begun to appear on titles of scientific articles. The development of the knowledge on the cardiocirculatory system and the principal steps of this fascinating subject were examined, with particular regard to microvascular bed and vessel sprouting, and to the intriguing observations on blood vessel neoformation that have been also made in the premicroscopic era. In Hunter's works, the concept of angiogenesis indeed emerges, but not the term "angiogenesis". The scientific language occurring during Hunter's time was still old-fashioned, and the term "angiogenesis" was not one of those he used, rather a much later neologism that sounds too modern to appear in that context. Would the first appearance of the term "angiogenesis" occur in late nineteenth century in studies dealing with embryogenesis and organ vascularization? The present study aims to explore the scientific literature and to open a debate to better define this matter.

T11 target structure induced modulations of the pro-inflammatory and anti-infammatorycytokine expressions in experimental animals for glioma abrogation.

Glioma angiogenesis is the result of the interaction between cancer cells with endothelial cells, and the surrounding inflammatory cells. This interaction plays a crucial role in directing the neo-formation of blood vessels. In the carcinogenic milieu, inflammatory cytokines secreted from inflammatory cells affect endothelial cell functions that are indispensable for tumor growth and metastatic propagation. TNF-α, referred to as the 'inflammatory switch', has shown its potential as an inflammatory agent by activation of IL-8 and IL-6 through NF-κB mediated pathway. Therefore, inhibitors of angiogenesis appear to be promising therapeutic agents for advanced gliomas. Previous studies from our lab showed that T11TS, a membrane glycoprotein, has antiangiogenic and antineoplastic activities in experimental animals and human samples. The present experimental study was designed to evaluate the effect of T11TS therapy on inflammatory cytokine expression of TNF-α, IL-8, IL-6 and their downstream associated molecule NF-κB in vivo. Our results revealed that T11TS therapy induced downregulation of TNF-α, IL-8, IL-6, and NF-κB confirmed by FACS assay and ELISA. In situ-immunofluorescence results hint that T11TS has the efficacy to stop the inflammation related to angiogenesis. Moreover, upregulation of IL-4 and IL-10 in microglia after T11TS therapy helps in complete abrogation of glioma inflammation and angiogenesis. These effects might contribute to the antineoplastic activity of T11TS.

Effects of the Histone Deacetylase Inhibitor Valproic Acid on Human Pericytes In Vitro

Microvascular pericytes are of key importance in neoformation of blood vessels, in stabilization of newly formed vessels as well as maintenance of angiostasis in resting tissues. Furthermore, pericytes are capable of differentiating into pro-fibrotic collagen type I producing fibroblasts. The present study investigates the effects of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) on pericyte proliferation, cell viability, migration and differentiation. The results show that HDAC inhibition through exposure of pericytes to VPA in vitro causes the inhibition of pericyte proliferation and migration with no effect on cell viability. Pericyte exposure to the potent HDAC inhibitor Trichostatin A caused similar effects on pericyte proliferation, migration and cell viability. HDAC inhibition also inhibited pericyte differentiation into collagen type I producing fibroblasts. Given the importance of pericytes in blood vessel biology a qPCR array focusing on the expression of mRNAs coding for proteins that regulate angiogenesis was performed. The results showed that HDAC inhibition promoted transcription of genes involved in vessel stabilization/maturation in human microvascular pericytes. The present in vitro study demonstrates that VPA influences several aspects of microvascular pericyte biology and suggests an alternative mechanism by which HDAC inhibition affects blood vessels. The results raise the possibility that HDAC inhibition inhibits angiogenesis partly through promoting a pericyte phenotype associated with stabilization/maturation of blood vessels.

Morphologic features of biocompatibility and neoangiogenesis onto a biodegradable tracheal prosthesis in an animal model

We evaluated a newly designed bioresorbable polymer (Degrapol) tracheal prosthesis in an in-vivo angiogenesis-inducing animal model focusing on the specific tissue reaction, the neo-angiogenesis and also the eventual cathepsin B role during the polymer degradation. Fifteen rabbits were divided into three groups (2, 6 and 8 weeks) and our tube-shaped porous prosthesis was implanted using the common carotid artery and the internal jugular vein as vascular pedicle. Optical and electron microscopy, immunohistochemistry and immunocytochemistry were performed at the end of each period, showing cells and fibrils, in direct contact with the Degrapol scaffold, strongly increased with time. Blood vessel neoformation was visible with CD31 expression localized at the endothelial cells forming the neovascular walls. Over time many of them differentiate in muscle fibers as validated by the expression of alpha-smooth muscle actin (SMA). Few inflammatory cells, expressing CD14, were visible while most cells adopting a pronounced spreading phenotype showed a strong positivity for cathepsin B. We concluded that this bioresorbable polymer provided a good substrate for fibrous tissue deposition with an excellent degree of neo-angiogenesis. Also, cathepsin B seems to contribute to the polymer degradation and particularly to neovascularization by stimulating capillary-like tubular structures and cell proliferation.

Ovarian Follicle Vascularization in Mammals with Special Regard to Domestic Animals

G. Macchiarelli*, A. Martelli**, V. Russo**, P. Berardinelli**, M.G. Palmerini*, S.A. Nottola***, J.Y. Jiang**** and E. Sato***** * Department of Experimental Medicine, University of L’Aquila, Italy ** Department of Comparative Biomedical Sciences, University of Teramo, Italy *** Department of Anatomy, University of Rome La Sapienza, Italy **** Ottawa Health Research Institute, Ottawa Hospital, Ontario, Canada ***** Lab. of Animal Reproduction, Faculty of Agriculture, Tohoku University of Sendai, Japan The ovarian function during reproductive life is related to a normal development of blood vessel neoformation and consequently to the expression of several factors that may upregulate/downregulate follicle and corpus luteum angiogenesis [1,2]. Follicle activation involves vascular endothelial growth factor production and increases blood vessels extension. Numerous morphological studies, mainly performed by means of vascular casting media, analysed the distribution and cyclical rearrangement of ovarian blood vessels in several mammals, in different experimental conditions [3]. Despite the wide literature on the blood vessel distribution in the mammalian ovary, only a few information is available on ovarian angiogenic morphological aspects of developing and atretic follicles, especially in domestic animals, that shows morphofunctional characteristics of the ovarian follicle more similar to humans than rodent models. In addition, it is not yet clear which morphological aspects are related to a correct angiogenesis and capillary regression, especially when evaluated in the light of species differences. Therefore, in order to better understand the morphological mechanisms regulating the microvascular changes occurring in the theca layer before ovulation of larger follicles, we have reviewed by scanning electron microscopy (SEM) of vascular corrosion casts (VCC) the ovarian microvasculature in different experimental conditions, in rodents and domestic animals. Rat, rabbit, pig, sheep, and cow ovaries, at different reproductive stages and or/subjected to different protocols of hormonal stimulation were studied. Rat model was used as control. Rabbit was chosen as a model for reflex ovulation [4]; pig [2,5,6] and sheep [7] as multiovulatory species and cow [8] as a monovulatory model similar to humans. SEM of CC was adopted because it is one of the technique of choice for 3D visualization of blood vessels and capillary network arrangements [4]. Methods and hormonal protocols were previously described [2, 4-9]. An intensive functional and morphological remodeling of cortical venules and arterioles accompanied follicle development [9]. Follicle angiogenesis was demonstrated during follicular maturation in all species studied [3]. SEM of VCC demonstrated the differentiation of several microstructures, namely buds, sprouts (sprouting angiogenesis) and intussusceptions (non sprouting angiogenesis) that allowed firstly the growth, then the duplication and multiplication of the preexisting capillaries. The gradual formation of a dense sinusoidal network supplying the theca layer of fully developed follicles (dominant) was also clearly shown. Atretic and subordinated follicles presented degenerative microvascular structures such as thinned capillaries and avascular areas. Species differences were related to follicle size and to mechanisms of follicle selection. In rodents, significant angiogenic morphological figures were mainly confined to the capillaries of the inner thecal layer. In larger follicles of domestic animals vascular remodeling and angiogenic

Effects of locally applied vascular endothelial growth factor (VEGF) and VEGF-inhibitor to the rabbit tibia during distraction osteogenesis

Introduction: Therapeutic angiogenesis, a novel concept in tissue engineering, is neo-formation of blood vessels in a tissue upon delivery of an angiogenic growth factor to the tissue. We hypothesised that therapeutic angiogenesis could enhance bone formation and challenged the hypothesis in an experimental model of distraction osteogenesis. Methods: Rabbits, divided into three equal groups of 12, had their right tibia lengthened by distraction osteogenesis. A mini-osmotic pump delivered to the osteotomy gap either recombinant human vascular endothelial growth factor (VEGF), VEGF-inhibitor, or vehicle alone during the latency and distraction phase. After consolidation, we assessed bone blood flow by radioactive microsphere entrapment, measured torsional stiffness and bone mineral content, and did histomorphometry. Results: VEGF and VEGF-inhibitor treatment failed to influence bone blood flow, torsional stiffness, bone mineral content and histomorphometric indices of the bone regenerate. However, VEGF treatment increased the blood flow in bone of the distracted limb and VEGF-inhibitor treatment decreased bone blood flow. Conclusion: The regenerate was unresponsive to VEGF and VEGF-inhibitor treatment in contrast to the neighbouring bone, which implies different biological properties of the vasculature in native and regenerating bone. VEGF is not recommended for enhancement of bone formation in this setting.

Angiogenesis in hematologic malignancies and its clinical implications.

Angiogenesis is defined as a neoformation of blood vessels of capillary origin. Hematopoiesis is closely linked with angiogenesis, for they share a common ancestor, the hemangioblast. Although it is well established that growth in solid tumors is dependent on angiogenesis, its role in hematologic malignancies has not yet been clarified. In this review, the direct evidence, ie, increased microvessel density, and the indirect evidence, ie, elevated level of angiogenic factors or overexpression of messenger RNA or protein of angiogenic factors, for and against the role of angiogenesis in the development and progression of hematologic malignancies are presented.

Enhancement of angiogenesis in regenerating gastrocnemius muscle of the toad (Bufo viridis) by low-energy laser irradiation

The effect of low-energy laser (He-Ne) irradiation on the process of neoformation of blood capillaries during regeneration in the toad (Bufo viridis) gastrocnemius muscle was studied using histomorphometric methods. The injured zones of the experimental toads were subjected to four direct He-Ne laser irradiations (632.8 nm wavelength; 6.0 mW for 2.3 min) every alternate day, commencing on the second day after injury. Muscles that were injured as above and subjected to red light irradiation served as control. The volume density (cm3/cm3) of the capillaries in the injured zone at 9 days after injury was significantly (P < 0.01) higher (0.09 +/- 0.006) than in the control muscles (0.048 +/- 0.007). At 14 days after injury, the volume density in the injured zone of the control muscles further increased, while the value in the laser-irradiated muscles remained unchanged. The surface density (m2/cm3) of the capillaries in the injured zone was 2.3-fold higher in the laser-irradiated muscles than in the control muscles at 9 days after injury. The surface density further increased in the control muscles between 9 and 14 days after injury, while in the laser-irradiated muscles there was a decrease in this value during the above period. The surface-to-volume ratios of the capillaries in the injured zone of control and laser-irradiated muscles indicate a straighter, rather than a convoluted appearance between 9 and 14 days after injury. It is concluded that He-Ne laser irradiation during skeletal muscle regeneration in the toad markedly promotes the process of neoformation of blood vessels in the injured zone.(ABSTRACT TRUNCATED AT 250 WORDS)

Neoformation of blood vessels in association with rat lung fibrosis induced by bleomycin.

We have used intratracheal instillation of bleomycin in rats to study the microanatomical changes of blood vessels associated with lung fibrosis. Bleomycin is a toxic cytostatic drug employed in classical models of lung fibrosis. Wistar rats were submitted to intratracheal injection of 1.5 units of bleomycin and sacrificed 2.5 months later, a timing when marked fibrosis of the lung is observed. We casted the vascular tree of the rat lungs by perfusion with a methacrylate resin. These casts were studied by scanning electron microscopy. Lung tissue was also studied by light microscopy and thin section electron microscopy. The major vascular modifications observed in the bleomycin-treated rats were: (1) neoformation of an elaborate network of vessels located in the peribronchial domains of the lung, and (2) distortion of the architecture of alveolar capillaries. By light microscopy, it was clear that the newly formed vascular network was located in regions of fibrosis (which in the resin casts were digested away). These neoformed vessels appeared to originate from bronchial arteries. Thin section electron microscopy revealed that endothelial cells of the neoformed vessels were plump, presented large nuclei, and showed numerous pinocytotic vesicles that were also observed in subendothelial pericytes. The alveoli of the bleomycin-treated rats were heterogeneous in size and shape in contrast with the homogeneity of alveoli of control animals. The alveolar capillaries of fibrotic lungs appeared to occupy a larger volume of the alveolar wall than alveolar capillaries of control rats. Our findings indicate that lung fibrosis encompasses marked changes of the vascular system, namely, the neoformation of vessels and the rearrangement of alveolar capillaries. These structural changes suggest that fibrotic transformation of the lung is associated with the local generation of angiogenic stimuli.

Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.

The development of new blood vessels (angiogenesis) is required for many physiological processes including embryogenesis, wound healing and corpus luteum formation. Blood vessel neoformation is also important in the pathogenesis of many disorders, particularly rapid growth and metastasis of solid tumours. There are several potential mediators of tumour angiogenesis, including basic and acidic fibroblast growth factors, tumour necrosis factor-alpha and transforming factors-alpha and -beta. But it is unclear whether any of these agents actually mediates angiogenesis and tumour growth in vivo. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and an angiogenesis inducer released by a variety of tumour cells and expressed in human tumours in situ. To test whether VEGF may be a tumour angiogenesis factor in vivo, we injected human rhabdomyosarcoma, glioblastoma multiforme or leiomyosarcoma cell lines into nude mice. We report here that treatment with a monoclonal antibody specific for VEGF inhibited the growth of the tumours, but had no effect on the growth rate of the tumour cells in vitro. The density of vessels was decreased in the antibody-treated tumours. These findings demonstrate that inhibition of the action of an angiogenic factor spontaneously produced by tumour cells may suppress tumour growth in vivo.

Effects of Exogenous Heparin on the Vasculogenesis of the Chorioallantoic Membrane

On the basis of the well-known stimulating role played by heparin on blood vessel neoformation in the chorioallantoic membrane (CAM), demonstrated by means of slow-release polymers soaked in this substance and placed on CAMs, a new technique of introducing heparin directly into the allantoic sac is proposed. According to observations carried out in ovo and after fixation, morphological modifications are demonstrated in the developing vasculature of the heparin-treated CAMs which, compared with the control CAMs, show dilated and sinuous arterial and venous branches, denser and irregular capillary networks, and a high number of vascular primordia. The results, confirming that heparin is involved in angiogenesis, indicate the suitability of the technique and suggest that the effects of this substance could be enhanced by growth factors released by CAM tissues rapidly growing up from the 5th to the 7th incubation day.