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Gene expression profiles identify a role for cyclooxygenase 2-dependent prostanoid generation in BMP6-induced angiogenic responses.

ABSTRACT: The bone morphogenetic protein (BMP) family of proteins participates in regulation of angiogenesis in physiologic and pathologic conditions. To investigate the molecular mechanisms that contribute to BMP-dependent angiogenic signaling, we performed gene expression profiling of BMP6-treated mouse endothelial cells. We detected 77 mRNAs that were differentially regulated after BMP6 stimulation. Of these, cyclooxygenase 2 (Cox2) was among the most highly up-regulated by BMP stimulation, suggesting a role for Cox2 as a downstream regulator of BMP-induced angiogenesis. Up-regulation of Cox2 by BMP6 was detected at both mRNA and protein levels in endothelial cells, and BMP6 increased production of prostaglandins in a Cox2-dependent fashion. BMP6 up-regulated Cox2 at the transcriptional level through upstream SMAD-binding sites in the Cox2 promoter. Pharmacologic inhibition of Cox2, but not Cox1, blocked BMP6-induced endothelial cell proliferation, migration, and network assembly. BMP6-dependent microvessel outgrowth was markedly attenuated in aortic rings from Cox2-/- mice or after pharmacologic inhibition of Cox2 in aortas from wild-type mice. These results support a necessary role for Cox2 in mediating proangiogenic activities of BMP6. These data indicate that Cox2 may serve as a unifying component downstream from disparate pathways to modulate angiogenic responses in diseases in which neovascularization plays an underlying pathophysiologic role.

SUBMITTER: Ren R

PROVIDER: S-EPMC1852219 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Gene expression profiles identify a role for cyclooxygenase 2-dependent prostanoid generation in BMP6-induced angiogenic responses.

Ren Rongqin R Charles Peter C PC Zhang Chunlian C Wu Yaxu Y Wang Hong H Patterson Cam C

Blood 20070401 7

The bone morphogenetic protein (BMP) family of proteins participates in regulation of angiogenesis in physiologic and pathologic conditions. To investigate the molecular mechanisms that contribute to BMP-dependent angiogenic signaling, we performed gene expression profiling of BMP6-treated mouse endothelial cells. We detected 77 mRNAs that were differentially regulated after BMP6 stimulation. Of these, cyclooxygenase 2 (Cox2) was among the most highly up-regulated by BMP stimulation, suggesting ...[more]

PMID: 17119124

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Project description:Intraventricular haemorrhage is a major complication of prematurity that results in neurological dysfunctions, including cerebral palsy and cognitive deficits. No therapeutic options are currently available to limit the catastrophic brain damage initiated by the development of intraventricular haemorrhage. As intraventricular haemorrhage leads to an inflammatory response, we asked whether cyclooxygenase-2, its derivative prostaglandin E2, prostanoid receptors and pro-inflammatory cytokines were elevated in intraventricular haemorrhage; whether their suppression would confer neuroprotection; and determined how cyclooxygenase-2 and cytokines were mechanistically-linked. To this end, we used our rabbit model of intraventricular haemorrhage where premature pups, delivered by Caesarian section, were treated with intraperitoneal glycerol at 2 h of age to induce haemorrhage. Intraventricular haemorrhage was diagnosed by head ultrasound at 6 h of age. The pups with intraventricular haemorrhage were treated with inhibitors of cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-?; and cell-infiltration, cell-death and gliosis were compared between treated-pups and vehicle-treated controls during the first 3 days of life. Neurobehavioural performance, myelination and gliosis were assessed in pups treated with cyclooxygenase-2 inhibitor compared to controls at Day 14. We found that both protein and messenger RNA expression of cyclooxygenase-2, prostaglandin E2, prostanoid receptor-1, tumour necrosis factor-? and interleukin-1? were consistently higher in the forebrain of pups with intraventricular haemorrhage relative to pups without intraventricular haemorrhage. However, cyclooxygenase-1 and prostanoid receptor 2-4 levels were comparable in pups with and without intraventricular haemorrhage. Cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-? inhibition reduced inflammatory cell infiltration, apoptosis, neuronal degeneration and gliosis around the ventricles of pups with intraventricular haemorrhage. Importantly, cyclooxygenase-2 inhibition alleviated neurological impairment, improved myelination and reduced gliosis at 2 weeks of age. Cyclooxygenase-2 or prostanoid receptor-1 inhibition reduced tumour necrosis factor-? level, but not interleukin-1?. Conversely, tumour necrosis factor-? antagonism did not affect cyclooxygenase-2 expression. Hence, prostanoid receptor-1 and tumour necrosis factor-? are downstream to cyclooxygenase-2 in the inflammatory cascade induced by intraventricular haemorrhage, and cyclooxygenase-2-inhibition or suppression of downstream molecules--prostanoid receptor-1 or tumour necrosis factor-?--might be a viable neuroprotective strategy for minimizing brain damage in premature infants with intraventricular haemorrhage.

Dataset Information

Gene expression profiles identify a role for cyclooxygenase 2-dependent prostanoid generation in BMP6-induced angiogenic responses.

Publications

Gene expression profiles identify a role for cyclooxygenase 2-dependent prostanoid generation in BMP6-induced angiogenic responses.

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