Abstract
BackgroundStudies of cerebral ischemia and other neuroinflammatory states have demonstrated a strong association between new vessel formation and microglial recruitment and activation, raising the possibility that microglia may be involved in promoting angiogenesis. As endothelial cell proliferation is a fundamental early step in angiogenesis, the aim of this study was to test this hypothesis by examining the influence of microglial secreted factors on brain endothelial cell (BEC) proliferation using BrdU incorporation.MethodsPrimary cultures of mouse BEC, microglia and astrocytes were used in this study. Proliferation of BEC was examined by BrdU incorporation. ELISA was used to quantify TNF and TGF-β1 levels within cell culture supernatants.ResultsMicroglia regulated BEC proliferation in a biphasic manner; microglia conditioned medium (MG-CM) from resting microglia inhibited, while that from activated microglia promoted BEC proliferation. A screen of microglial cytokines revealed that BEC proliferation was inhibited by TGF-β1, but promoted by TNF. ELISA showed that TNF and TGF-β1 were both present in MG-CM, and that while TGF-β1 dominated in resting MG-CM, TNF levels were massively increased in activated MG-CM, shifting the balance in favor of TNF. Antibody-blocking studies revealed that the influence of MG-CM to inhibit or promote BEC proliferation was largely attributable to the cytokines TGF-β1 and TNF, respectively.ConclusionThis data suggests that microglial activation state might be an important determinant of cerebral angiogenesis; inhibiting BEC proliferation and neovascularization in the normal central nervous system (CNS), but stimulating the growth of new capillaries under neuroinflammatory conditions.
Highlights
Studies of cerebral ischemia and other neuroinflammatory states have demonstrated a strong association between new vessel formation and microglial recruitment and activation, raising the possibility that microglia may be involved in promoting angiogenesis
This data suggests that in vivo, microglial activation state might be an important determinant of the earliest stage of cerebral angiogenesis, namely endothelial cell yet been directly tested in the ischemic central nervous system (CNS), traumatic CNS injury leads to activation of microglia and macrophages, and drugs that block activation and proliferation of these cells, inhibit neovascularization [25]
Our data demonstrate that microglia regulate brain endothelial cell (BEC) proliferation in a biphasic manner; microglia conditioned medium (MG-CM) from resting microglia inhibit, while that from activated microglia promote BEC proliferation
Summary
Studies of cerebral ischemia and other neuroinflammatory states have demonstrated a strong association between new vessel formation and microglial recruitment and activation, raising the possibility that microglia may be involved in promoting angiogenesis. Angiogenesis occurs in the central nervous system (CNS) not just during development [1], and in pathological conditions, including cerebral ischemia [2], neoplasia [3], and neuroinflammation [4,5]. Angiogenesis is regulated by a plethora of factors, including growth factors [6], cytokines [7], and extracellular matrix (ECM) molecules [8]. In addition to soluble factors, ECM proteins provide important instructional cues in angiogenesis [11], and recent work from our laboratory showing that fibronectin is strongly induced on angiogenic capillaries in the hypoxic CNS [12], as well as on angiogenic vessels in the developing CNS [13], suggests that this protein may be important for cerebral angiogenesis
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