The therapeutic potential of placental growth factor (PlGF) and its receptor Flt1 in angiogenesis is poorly understood. Here, we report that PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to vascular endothelial growth factor (VEGF). An antibody against Flt1 suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in autoimmune arthritis. Anti-Flt1 also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not attributable to reduced plaque neovascularization. Inhibition of VEGF receptor Flk1 did not affect arthritis or atherosclerosis, indicating that inhibition of Flk1-driven angiogenesis alone was not sufficient to halt disease progression. The anti-inflammatory effects of anti-Flt1 were attributable to reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood; impaired infiltration of Flt1-expressing leukocytes in inflamed tissues; and defective activation of myeloid cells. Thus, PlGF and Flt1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.
The molecular pathways involved in the differentiation of hematopoietic progenitors are unknown. Here we report that chemokine-mediated interactions of megakaryocyte progenitors with sinusoidal bone marrow endothelial cells (BMECs) promote thrombopoietin (TPO)-independent platelet production. Megakaryocyte-active cytokines, including interleukin-6 (IL-6) and IL-11, did not induce platelet production in thrombocytopenic, TPO-deficient (Thpo(-/-)) or TPO receptor-deficient (Mpl(-/-)) mice. In contrast, megakaryocyte-active chemokines, including stromal-derived factor-1 (SDF-1) and fibroblast growth factor-4 (FGF-4), restored thrombopoiesis in Thpo(-/-) and Mpl(-/-) mice. FGF-4 and SDF-1 enhanced vascular cell adhesion molecule-1 (VCAM-1)- and very late antigen-4 (VLA-4)-mediated localization of CXCR4(+) megakaryocyte progenitors to the vascular niche, promoting survival, maturation and platelet release. Disruption of the vascular niche or interference with megakaryocyte motility inhibited thrombopoiesis under physiological conditions and after myelosuppression. SDF-1 and FGF-4 diminished thrombocytopenia after myelosuppression. These data suggest that TPO supports progenitor cell expansion, whereas chemokine-mediated interaction of progenitors with the bone marrow vascular niche allows the progenitors to relocate to a microenvironment that is permissive and instructive for megakaryocyte maturation and thrombopoiesis. Progenitor-active chemokines offer a new strategy to restore hematopoiesis in a clinical setting.
The incidence of Alzheimer disease (AD) and vascular dementia is greatly increased following cerebral ischemia and stroke in which hypoxic conditions occur in affected brain areas. -Amyloid peptide (A), which is derived from the -amyloid precursor protein (APP) by sequential proteolytic cleavages from -secretase (BACE1) and presenilin-1 (PS1)/␥-secretase, is widely believed to trigger a cascade of pathological events culminating in AD and vascular dementia. However, a direct molecular link between hypoxic insults and APP processing has yet to be established. Here, we demonstrate that acute hypoxia increases the expression and the enzymatic activity of BACE1 by up-regulating the level of BACE1 mRNA, resulting in increases in the APP C-terminal fragment- (CTF) and A. Hypoxia has no effect on the level of PS1, APP, and tumor necrosis factor-␣-converting enzyme (TACE, an enzyme known to cleave APP at the ␣-secretase cleavage site). Sequence analysis, mutagenesis, and gel shift studies revealed binding of HIF-1 to the BACE1 promoter. Overexpression of HIF-1␣ increases BACE1 mRNA and protein level, whereas down-regulation of HIF-1␣ reduced the level of BACE1. Hypoxic treatment fails to further potentiate the stimulatory effect of HIF-1␣ overexpression on BACE1 expression, suggesting that hypoxic induction of BACE1 expression is primarily mediated by HIF-1␣. Finally, we observed significant reduction in BACE1 protein levels in the hippocampus and the cortex of HIF-1␣ conditional knock-out mice. Our results demonstrate an important role for hypoxia/HIF-1␣ in modulating the amyloidogenic processing of APP and provide a molecular mechanism for increased incidence of AD following cerebral ischemic and stroke injuries.An important pathologic feature of Alzheimer disease (AD) 4 is formation of extracellular senile plaques in the brain, whose major components are small peptides called -amyloid (A) derived from -amyloid precursor protein (APP). APP is sequentially cleaved first by the -secretase (-site amyloid precursor protein cleaving enzyme, BACE) and then by the ␥-secretase complex (including presenilin, nicastrin, APH-1, and PEN-2) to generate the heterogeneous A species, mostly A40 but also the more deleterious A42. Alternatively, APP can be cleaved by ␣-secretase within the A domain to generate non-amyloidogenic soluble APP␣ (sAPP␣) (1-3). The exact ␣-secretase is not known, but a disintegrin and metalloprotease domain 10 (ADAM10) and TNF-␣-converting enzyme (TACE) are two likely candidates (4, 5). It is widely believed that A overproduction directly or indirectly initiates a cascade of neurodegenerative steps resulting in formation of senile plaques, neurofibrillary tangles, and neuronal loss, which characterize AD (6). Hence analysis of cellular regulation affecting A generation, including identification of factors regulating the level/ activity of APP cleavage enzymes, should provide invaluable information for AD therapeutic intervention.BACE is a membrane-bound aspartic protease whose activity is t...
Alzheimer's disease (AD) is characterized by the accumulation of cerebral plaques composed of 40- and 42-amino acid beta-amyloid (Abeta) peptides, and autosomal dominant forms of AD appear to cause disease by promoting brain Abeta accumulation. Recent studies indicate that postmenopausal estrogen replacement therapy may prevent or delay the onset of AD. Here we present evidence that physiological levels of 17beta-estradiol reduce the generation of Abeta by neuroblastoma cells and by primary cultures of rat, mouse and human embryonic cerebrocortical neurons. These results suggest a mechanism by which estrogen replacement therapy can delay or prevent AD.
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