Expression of angiogenesis factors and selected vascular wall matrix proteins in intracranial saccular aneurysms.

OBJECTIVE: Little is known about the biological mechanisms associated with the genesis, growth, and rupture of intracranial saccular aneurysms. It is postulated that the vascular wall pathological response of aneurysmal disease is associated with abnormal angiogenesis factor expression. METHODS: We have examined the expression and distribution of immunoreactivity to angiogenesis growth factors (vascular endothelial growth factor and basic fibroblast growth factor) and selected vascular wall matrix proteins (fibronectin, Type IV collagen, and alpha smooth muscle actin) in the walls of human intracranial aneurysms from surgical biopsy or autopsy specimens. Double antibody immunohistochemical stains were performed in contiguous fixed sections from three control circle of Willis arteries, five berry aneurysms, four giant aneurysms, and one mycotic aneurysm (three unruptured and seven ruptured lesions). RESULTS: The aneurysmal wall exhibited diffuse disorganized expression of matrix proteins as compared to their organization in control vessels. There was strong patchy expression of vascular endothelial growth factor within the walls of all aneurysms, including marked staining of capillaries and small vessels within the thickened walls of giant lesions. The expression of basic fibroblast growth factor was more diffuse and occurred around the fibrocytes and myocytes within the disrupted media of 9 of 10 aneurysms. CONCLUSIONS: These results confirm the gross architectural molecular disruption in the walls of intracranial aneurysms and illustrate an apparent biological response involving angiogenesis factors. Further research should elucidate the time course and possible causal relationships of these changes to aneurysm growth and rupture with the aim of possible therapeutic manipulation.

Expression of angiogenic factors and structural proteins in central nervous system vascular malformations.

Little is known of the molecular mechanisms mediating the genesis and subsequent biological behavior of central nervous system vascular malformations. The role of angiogenic and permeability-inducing factors in the pathogenesis of these lesions has not bee previously explored. In this study, we subject specimens from 12 cases of excised vascular malformation to a battery of immunostaining for vascular endothelial growth factor, basic fibroblast growth factor, and selected structural and matrix proteins. The lesions consisted of seven arteriovenous malformations (AVMs), including one angiographically occult AVM, one arterialized vein from a dural AVM, and five cavernous malformations (CMs). Vascular endothelial growth factor was expressed by all lesions and was localized predominantly in the subendothelial layer and in perivascular spaces. Four of seven AVMs and four of five CMs demonstrated faint basic fibroblast growth factor expression that was localized to the media of AVM vessels and the subendothelial layer and intercavernous matrix of CMs. This pattern of angiogenic factor immunostaining was correlated with the expression of structural and matrix proteins in the same lesions. Laminin was not expressed in any of the CMs, confirming previous reports from our laboratory. By contrast, fibronectin expression was more prominent in CMs than in AVMs. Collagen Type IV and alpha smooth muscle actin expression occurred in every lesion. We conclude that angiogenic growth factors are expressed in all types of vascular malformations of the central nervous system. The pattern of expression suggests diffuse activation of angiogenesis without specific relation to individual vessel types or recent clinical behavior. Defining the role of angiogenesis in vascular malformations might provide insight into their pathogenesis and suggest novel strategies for modification of their behavior.

Vascular endothelial growth/permeability factor expression in human glioma specimens: correlation with vasogenic brain edema and tumor-associated cysts.

Peritumoral vasogenic brain edema (PVBE) is a common accompaniment of malignant gliomas. It results from microvascular extravasation of plasma fluid and proteins through the interendothelial spaces. Tumor-associated cysts (TACs) are observed more commonly with benign gliomas that are not associated with PVBE. This study investigates the hypothesis that these morphologically distinct epiphenomena of microvascular extravasation are linked by a common pathophysiological mechanism involving vascular endothelial growth/permeability factor (VEG/PF), which has been implicated in vascular leak phenomena including ascites, malignant effusions, and brain edema. Furthermore, VEG/PF has been isolated from cultured glioma cells, and both VEG/PF protein and messenger RNA transcripts are expressed in brain tumor tissue. To further elucidate the relationship of VEG/PF to PVBE and TACs, the authors examined 34 pathological specimens for VEG/PF expression. Nineteen primary low-grade tumors, 11 primary high-grade tumors, and four gliosis controls were immunostained with a polyclonal anti-VEG/PF immunoglobulin G antibody. Magnetic resonance imaging was used to quantitate PVBE and to determine the presence of TACs and tumor enhancement. The study revealed that eight VEG/PF-negative specimens exhibited no significant edema, whereas 26 VEG/PF-positive tumors exhibited either significant PVBE or TACs. Notably, eight of nine benign TACs that were not associated with PVBE immunostained positive for VEG/PF. These data indicate a high degree of correlation between VEG/PF expression by gliomas and the occurrence of PVBE or TACs, irrespective of tumor grade, thus supporting VEG/PF's pivotal role as the common pathophysiological link between these processes.

Vascular permeability factor in brain metastases: correlation with vasogenic brain edema and tumor angiogenesis.

Metastatic brain tumors are almost always associated with vasogenic brain edema, which in turn plays a pivotal role in the evolution of neurological morbidity associated with these lesions. Attention has recently focused on a group of proteinaceous vascular permeability factors (VPF's) that are capable of inducing angiogenesis and promoting increased capillary permeability. To test the hypothesis that metastatic brain tumors expressing VPF's are associated with peritumoral cerebral edema, a rabbit polyclonal immunoglobulin (Ig) G anti-VPF was used to immunostain pathological specimens of metastatic cerebral tumors obtained from 22 patients who underwent surgery at Yale-New Haven Hospital. Magnetic resonance (MR) imaging was used to correlate VPF staining in tumor tissue with the occurrence of peritumoral brain edema. A histological study of the microvasculature was then conducted by immunostaining the specimens for endothelial cell factor VIII surface antigen, using two gliosis specimens as controls. Results revealed 21 of 22 tumors stained positively for VPF's; the negative-VPF tumor was a melanoma that exhibited no peritumoral edema. Twenty of 22 tumors had MR imaging-evident vasogenic edema. The presence and intensity of VPF immunostaining of microvascular features were noted and compared. Factor VIII staining demonstrated tumor vascularity to be most abundant in VPF-rich regions of tumor. The authors therefore report a high correlation between the presence of VPF's and the occurrence of peritumoral brain edema associated with cerebral metastases.

An analysis of changing trends in philosophies of science on nursing theory development and testing.

The effects of changing trends in philosophies of science on nursing theory development and testing are analyzed. Two philosophies of science--logical empiricism and historicism--are compared for four variables: (1) components of science, (2) conception of science, (3) assessment of scientific progress, and (4) goal of philosophy of science. These factors serve as the basis for assessing trends in the development and testing of nursing theory from 1964 to the present. The analysis shows a beginning philosophic shift within nursing theory from logical empiricism to historicism and addresses implications and recommendations for future nursing theory development and testing.