Expression of Angiogenic Factors and Structural Proteins in Central Nervous System Vascular Malformations

Abstract

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.

Clinical progression and familial occurrence of cerebral cavernous angiomas: the role of angiogenic and growth factors

“…6,29,37,43,45,46,48 Our study confirms that cavernomas express the main growth factors involved in angiogenesis.…”

Cerebral arteriovenous malformations. Part 1: cellular and molecular biology

“…Arteriovenous malformations in the brain exhibit a mature vessel wall phenotype, as evidenced by intense laminin expression localized in and around the internal elastic lamina and the absence of significant fibronectin expression. 58,105 Fibronectin and laminin are found in basement membranes of normal vascular beds, providing structural support to the vessel wall by anchoring endothelial cells to the underlying internal elastic membrane and smooth muscle layers. The relative ratio of laminin to fibronectin expression provides a partial indicator of vessel wall maturity.…”

“…105 Pathological studies have shown that almost three-quarters of AVMs resected following incomplete embolization express VEGF and Flk-1, whereas the endothelium of only one-quarter of AVMs not preoperatively embolized expresses these factors. 121 This finding may explain why partially obliterated AVMs recur.…”

Increased expression of fibronectin and the α5β1 integrin in angiogenic cerebral blood vessels of mice subject to hypobaric hypoxia

“…The growth of new capillaries (angiogenesis) occurs in the central nervous system (CNS), not just during development (Marin-Padilla, 1985;Plate et al, 1994;Plate, 1999), but also in a number of conditions within the adult CNS, including brain tumors (Plate and Risau, 1995;Bello et al, 2004;Jansen et al, 2004), arterio-venous malformations (AVMs) (Rothbart et al, 1996;Uranashi et al, 2001), and cerebral ischemia (Garcia et al, 1971). Analysis of postmortem tissue of stroke patients has shown that cerebral ischemia stimulates the growth of new capillaries in areas surrounding the ischemic core, also known as the ischemic penumbra (Krupinski et al, 1994).…”