Received for publication July 5, 2007.
Revised September 5, 2007.
Accepted for publication September 10, 2007.

Transforming growth factor-1 impairs endothelin-1-mediated contraction of brain vessels via induction of mitogen-activated protein kinase phosphatase-1 and inhibition of p38 MAP kinase

Abstract

Brain levels of transforming growth factor-1 (TGF-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-1 (TGF⁺mice) display, with aging, selectively reduced endothelin-1 (ET-1)-mediated contractions. As ET-1 is a key regulator of cerebrovascular tone and homeostasis, we investigated how increased levels of TGF-1 could selectively alter this contractile response. We found that ET_A receptors, via activation of p38 MAP kinase, mediate the ET-1-induced contractions in mouse cerebral arteries, a response significantly decreased in aged TGF⁺ mice (-39%, p<0.01) despite unaltered ET_A receptor levels or affinity. In cerebrovascular smooth muscle cell cultures, chronic TGF-1 significantly decreased (>50%, p<0.05) the ET-1-induced activation of the p38 MAPK/heat shock protein 27 (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 chronic TGF-1 in modulating cerebrovascular tone by dampening ET-1-mediated activation of the p38 MAPK/HSP27 signaling pathway. Such changes in ET-1-mediated signaling may help maintain vascular wall homeostasis by compensating for the diminished dilatory function induced by TGF-1 and amyloid-, two molecules which brain levels are increased in patients with Alzheimer's disease.

Key words: Endothelin, P38 MAP Kinase, Func. analysis receptor/ion channel mutants