Transforming Growth Factor- (cid:1) 1 Impairs Endothelin-1-Mediated Contraction of Brain Vessels by Inducing Mitogen-Activated Protein (MAP) Kinase Phosphatase-1 and Inhibiting p38 MAP Kinase

Brain levels of transforming growth factor- (cid:1) 1 (TGF- (cid:1) 1) are increased in Alzheimer’s disease and have been implicated in the associated cerebrovascular pathology. We recently reported that transgenic mice that overexpress TGF- (cid:1) 1 (TGF (cid:1) mice) display, with aging, selectively reduced endothelin-1 (ET-1)- mediated contractions. Because ET-1 is a key regulator of cerebrovascular tone and homeostasis, we investigated how increased levels of TGF- (cid:1) 1 could selectively alter this contractile response. We found that ETA receptors, via activation of p38 mitogen-activated protein (MAP) kinase, mediate the ET-1-induced contraction in mouse cerebral arteries, a response significantly decreased in aged TGF (cid:1) mice ( (cid:2) 39%; p (cid:3) 0.01) despite unaltered ETA receptor levels or affinity. In cerebrovas- cular smooth muscle cell cultures, long-term treatment with TGF- (cid:1) 1 significantly decreased ( (cid:4) 50%; p (cid:3) 0.05) the ET-1-induced activation of the p38 MAPK/27-kDa heat shock protein (HSP27) signaling pathway. This occurred with no effect upstream to p38 MAP kinase but with the concomitant induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) expression. Inhibition of MKP-1 expression with Ro-31-8220 or suppression of MKP-1 expression by short interfering RNA restored the ET-1-mediated p38 MAP kinase response. These results disclose a new role for long-term increases transduction that 1 activation of the p38 MAPK/27-kDa shock protein (HSP27) pathway via expression of the transcriptionally regulated mitogen-activated protein kinase phosphatase-1 (MKP-1).

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