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The inner parts of the walls of large blood vessels do not normally contain intrinsic vasculature. In pathologic conditions such as arteriosclerosis or thrombosis, angiogenesis occurs, and may have significant clinical consequences. This review attempts to relate the little that is known about the factors specific to vascular walls which regulate angiogenesis to more general knowledge of the phenomenon.
Angiogenesis, a fundamental process in various physiological and pathological events, is generally studied using in vivo models, such as the chick chorioallantoic membrane or the rabbit cornea, which are difficult to quantitate. We developed the quantitation of angiogenesis in an in vivo model previously described by Dvorak et al [6]. Perforated plexiglass chambers filled with human or rat fibrin were implanted into the dorsal subcutaneous space of a Wistar rat. After four days of implantation, a sequentially organized invasion of the fibrin gel by various blood cell types occurred through the holes and neovascularized granulation tissue buds appeared. These buds presented mature neovessels and a new collagen matrix. Three dimensional computer image analysis of the chambers was performed using macroscopic and microscopic parameters: total vascularized area, bud height and equivalent diameter, number of vessels per bud and percentage of central vessels. The time course of the angiogenic response to rat or human fibrin gel was studied and 14 days was found to be the optimum period of implantation. The bud height and number of neovessels were not found to be significantly different when rat or human fibrin gels were used. This quantitative study was a prerequisite for further investigations of the effects of biological and pharmacological agents on angiogenesis.
The subject of contact lens-induced corneal vascularization has attracted considerable interest in recent times in view of the relatively high prevalence of this condition with the use of extended wear soft lenses. This paper reviews clinical features and underlying mechanisms of the vascular response to lens wear. The concept of a "normal" vascular response to contact lens wear is proposed; the limits of this response are defined and incorporated into a simple grading system. The clinical presentation of vessel growth in the cornea is described together with appropriate methods of slit lamp evaluation. Current theories of the pathology and etiology of lens-induced vascularization are reviewed, and a dual-etiology model of stromal vessel formation is described. It is concluded that the prognosis for halting the progression of vascularization is excellent; however, little information is available concerning the long-term regression of "ghost" vessels.
Recent fundamental research has disclosed the presence of multiple genetic alterations including activation of oncogenes and inactivation of tumor suppressor genes in various human cancers. These multiple genetic alterations are thought to be correlated with multiple stages of carcinogenesis and further progression. Hepatocellular carcinoma (HCC) is a typical example. The majority of HCCs are associated with infection by hepatitis virus B or C. In the damaged liver, small nodular lesions develop due to clonal expansion of hepatocytes. Some of these nodules are diagnosed as early HCC of the well differentiated type and correspond to in situ or microinvasive carcinoma. Within these nodules, moderately or poorly differentiated HCCs often emerge as nodule-in-nodule lesions when the diameter of the nodules exceeds 1.5 cm. Ordinary HCCs formed by progression show highly increased cell proliferation, neovascularization, production of high-molecular-mass forms of basic fibroblast growth factor and aneuploidy in some tumors. Corresponding to this stage of malignant progression, HCCs show loss of heterozygosity for multiple chromosomes including chromosomes 4, 16q and 17p. Tumor suppressor gene p53, located on 17p, is frequently mutated in high-grade, but not in early, HCCs. Thus, it is strongly suggested that inactivation of multiple tumor suppressor genes plays an important role in progression, and probably directly or indirectly causes chromosome instability, enhanced cell proliferation and neovascularization.
We induced intravitreal cellular proliferation by injection of carbon microparticles (size 20-70 nm) into the vitreous of 21 eyes of 11 cynomolgus monkeys. Pathological changes were evaluated by light and electron microscopy. At 1 week, there was conspicuous cyclitis showing exudative separation of the nonpigmented and pigmented ciliary epithelium, inflammatory cells, mononuclear phagocytes, and premacular vitreous detachment. At 3 weeks, continued macrophagic response was accompanied by fibrovascular proliferation with ingrowth of vessels from the ciliary body into the vitreous. At 4-5 weeks, deposition of extracellular fibrous material and traction retinal detachment (RD) were found. At 10 weeks, all eyes had extensive RD with pre- and subretinal collagenous cellular membranes. Carbon-laden macrophages were aggregated over the optic disc and fovea with prepapillary neovascularization and cystoid macular edema. Thus, intravitreal fibrovascular proliferation, vitreous contraction, and RD were induced by inflammatory and phagocytic response to carbon particles.
Fluorescent iridography evidenced that postthrombotic retinopathy is associated with pathologic changes in the iridal vessels, increase of the circulation time, impaired angioarchitectonics, development of shunts and collaterals, in some cases of new vessels. The degree of the pathologic changes in the iris correlates with the severity of the underlying condition. Extravasal release of fluorescein from the iridal and ciliary vessels evidences an impairment of the permeability of the anterior section of the ++hemato-ophthalmic barrier in postthrombotic retinopathy.
A 62-year-old man manifested multiple nodular growths in his left iris and unilateral glaucoma. Detailed clinical and pathologic studies showed that these lesions were adenomas derived from the spurs of Fuchs, Michel, and Grunert in the iris pigment epithelium. We suggest terming this newly described entity nodular adenomatosis of the iris pigment epithelium and propose a classification of primary neoplastic lesions of the iris.
Choroidal neovascularisation developed in 62/66 (94%) eyes followed up for a mean period of 11.2 years after treatment with xenon arc feeder vessel coagulation for proliferative sickle retinopathy (PSR). In 27 eyes the neovascularisation was chorioretinal alone and in 35 eyes choriovitreal. Chorioretinal neovascularisation (CRN) was a benign complication but may convert to choriovitreal neovascularisation (CVN). Late sequelae of CVN included vitreous haemorrhage, posterior vitreous face fibrosis, and tractional retinal detachment. Visual loss (of greater than or equal to 3 Snellen lines for greater than or equal to 3 months) occurred in nine eyes affected by choroidal neovascularisation, though because of other pathology this could not always be attributed to the choroidal neovascularisation. The incidence of visual loss in CVN affected eyes was significantly greater, by survival curve analysis, than in eyes affected by CRN alone. Permanent visual loss from tractional retinal detachment definitely attributable to CVN occurred in 2/35 (6%) eyes.
Examined were 91 eyes with non-proliferative and proliferative retinopathy with coexisting maculopathy in 51 patients in whom segmental or retinal pan-photocoagulation were performed. The period of observation--3 to 4.5 years. Stabilization of the pathological process was observed in 37.3 p.c. of cases, 54.9 p.c. of patients showed further deterioration and 7.6 p.c. loss of vision. The most frequent cause of deterioration was the progression of the macular lesions (72 p.c.), a smaller number of cases (28 p.c.) was due to other changes.
General principles of the description and functional evaluation of the morphological changes developing in the hemomicrocirculatory bed under pathological conditions are given. A necessity of dividing vascular, intra- and extravascular (stromal) changes into pathological and adaptive is underlined. A conclusion is made that such an approach to the characteristics of morphological transformations in the microcirculation system will provide a more deep insight into mechanisms of compensation of the terminal hemodynamics disorders and into the causes of a collapse of function of the local adaptive apparatus.
Proteolytic enzymes play a key role in a variety of physiological processes in which the degradation of macromolecules is essential: angiogenesis, embryogenesis, bone and tissue remodelling, blood hemostasis and cell migration. The action of these enzymes is also crucial in the development of many pathological conditions such as wound healing, neoplasia, inflammation and arthritic disorders. The activity of proteases is negatively affected by specific protease-inhibitors. Various growth factors and other cytokines modulate the synthesis and secretion of both proteases and protease-inhibitors. The study of this regulation results in a better insight into (patho)physiology at the molecular level and promises to result in alternative treatment strategies.
Remodelling tissues, in both normal and pathological situations, show a greatly increased synthesis and turnover of hyaluronan. An essential part of these processes is new blood vessel formation. Whereas native hyaluronan has been reported to inhibit angiogenesis in vivo, partial degradation products (4-25 disaccharide units) have been found to stimulate angiogenesis in several in vivo systems. Examination of the effect of hyaluronan and its oligosaccharides on cultured cells suggests that these effects are due to the direct action of hyaluronan on endothelial cells. Native HA inhibits endothelial cell proliferation and disrupts cell-cell/cell-substrate interactions at physiological concentration. Angiogenic oligosaccharides induce both endothelial proliferation and migration, possibly via a receptor-mediated mechanism. Thus the metabolic state of hyaluronan could have profound effects on tissue neovascularization.
A 5-day-old female patient was found to have large hereditary retinoblastomas in the posterior pole of each eye. The patient received radiation treatment over a 39-day period, with each retina receiving 4600 rad. Two weeks after the complete treatment the tumours had regressed to approximately one-quarter of their original size. By 14 weeks following completion of radiotherapy the patient had developed in each eye extensive iris neovascularisation with progressive closure of the filtration angles, secondary glaucoma, and retinal detachments resulting from fibrovascular proliferation on the retinal surface. Radiosensitivity studies were from separate conjunctival biopsies obtained before and after radiation. These showed a D0 (calculated survival curve parameters, defined in the Methods section) in the exponential growth phase of 110 prior to radiation and a postirradiation exponential growth phase D0 of 70. Karotype studies showed several chromosomal abnormalities following radiotherapy. The clinical course and pathology findings are thought to represent an unusually severe orbital and ocular response to radiation therapy. These findings are consistent with our hypothesis that some patients with hereditary retinoblastoma may have a defect in the accumulation repair of x-irradiation induced DNA damage.
The turnover of endothelium in a normal adult male is very low. Angiogenesis, the formation of new blood vessels, involves a high turnover of endothelial cells. It takes place during embryogenesis, ovulation and many pathological conditions, e.g. tumor growth. Soluble polypeptide growth factors for endothelial cells have been biochemically characterized. They are able to induce angiogenesis in vivo. Inhibitors of angiogenesis can inhibit tumor vascularization and the growth of solid tumors in mice. Tumor metastasis involves the migration of malignant tumor cells through endothelial cells. The organ and tissue specificity of these and other invasive migrations through vascular endothelium may be related to the heterogeneity and organ specificity of endothelial cells.
Senile macular degeneration (SMD) has several morphologic forms that may exist singly or in various combinations. Patients with drusen are at an increased risk to develop SMD. Types of drusen that have been recognized clinically and histopathologically include hard or nodular, soft, glistening or calcified, and diffuse. Hard drusen are probably a consequence of extrusion of material from one or a cluster of retinal pigment epithelial (RPE) cells. Soft drusen are a sign of more widespread disease of the RPE, develop in eyes with hard drusen, and represent small areas of serous detachment of the RPE and the thickened inner aspect of Bruch's membrane. RPE areolar atrophy can occur in the setting of hard and soft drusen and in larger RPE detachments. From the morphologic point of view, we propose that the process leading to disciform scar formation in SMD begins with thickening of the inner aspect of Bruch's membrane due to production of abnormal basement membrane by the RPE. This thickened area is weakly attached and allows the development of localized detachments (soft drusen). These localized detachments become confluent into large detachments of the RPE. Choroidal neovascularization occurs in association with diffuse and soft drusen and larger serous RPE detachments. Bleeding from neovascular tissue leads to disciform scar formation.
Angiogenesis is the process of generating new capillaries and leads, therefore, to vascularization of tissues. This process occurs during embryological development and during pathological and physiological conditions in adult life, including those involving the reproductive organs. Recent studies, in the field of tumour biology in particular, have led to the identification of several factors responsible for inducing angiogenesis and the elucidation of ways of modulating their activity. This review summarizes our knowledge of angiogenesis in the ovary, testis, endometrium and placenta, and suggests ways in which further research might contribute to a better understanding of the processes controlling reproduction and identify new approaches to the regulation of fertility.
Thyroid tissue was collected from 60 patients during operations for various thyroid conditions. The tissue's angiogenic capacity was assessed in a chick chorioallantoic membrane preparation. Angiogenic activity was observed in 22 (85%) of 26 solitary follicular neoplasms, in none of ten papillary carcinomas and in one of seven glands with Graves' disease (all pretreated with propranolol). Of 17 glands with euthyroid multinodular colloid goitre, three (18%) showed angiogenic activity. No angiogenic activity was detected in normal thyroid tissue from 26 patients. Angiogenic activity of diseased human thyroid does not seem to be a marker of thyroid malignancy.
Hematogenous metastasis is a major consideration in the staging, treatment and prognosis of patients with cancer. Key events affecting hematogeneous metastasis occur in the microvasculature. This is a brief, selective review of some interactions involving cancer cells and the microvasculature in pathologic sequence, specifically: (1) intravasation of cancer cells; (2) the arrest of circulating cancer cells in the microvasculature; (3) cancer cell trauma associated with arrest; (4) microvascular trauma; (5) the inflammatory; and (6) the hemostatic coagulative responses associated with arrest, and finally (7) angiogenesis, leading to tumor vascularization. The evidence shows that through a series of complex interactions with cancer cells, the microvasculature acts as a rate-regulator for the metastatic process, in addition to providing routes for cancer cell dissemination and arrest sites for cancer cell emboli.