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Acta Physiol (Oxf) ; 224(1): e13079, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29694711

RESUMO

AIM: Constitutive release of NO blunts intrinsic and stimulated contractile activity in cerebral arteries (CA). Here, we explored whether phosphorylation and expression levels of the PKG-sensitive, leucine zipper positive (LZ+ ) splice variants of the regulatory subunit of myosin phosphatase (MYPT1) are involved and whether its expression is associated with higher cGMP sensitivity. METHODS: Vascular contractility was investigated by wire myography. Phosphorylation of MYPT1 was determined by Western blotting. RESULTS: Constitutive phosphorylation of MYPT1-T696 and T853 was lower and that of S695 and S668 was higher in cerebral arteries from the circulus arteriosus (CA-w) than in femoral arteries (FA), while total MYPT1 expression was not different. In CA-w but not in FA, L-NAME lowered phosphorylation of S695/S668 and increased phosphorylation of T696/T853 and of MLC20 -S19, plus basal tone. The increase in basal tone was attenuated in CA-w and basilar arteries (BA) from heterozygous MYPT1-T696A/+ mice. Compared to FA, expression of the LZ+ -isoform was ~2-fold higher in CA-w coincident with a higher sensitivity to DEA-NONOate, cinaciguat and Y27632 in BA and 8-Br-cGMP (1 µmol/L) in pre-constricted (pCa 6.1) α-toxin permeabilized CAs. In contrast, 6-Bnz-cAMP (10 µmol/L) relaxed BA and FA similarly by ~80%. CONCLUSION: Our results indicate that (i) regulation of the intrinsic contractile activity in CA involves phosphorylation of MYPT1 at T696 and S695/S668, (ii) the higher NO/cGMP/PKG sensitivity of CAs can be ascribed to the higher expression level of the LZ+ -MYPT1 isoform and (iii) relaxation by cAMP/PKA pathway is less dependent on the expression level of the LZ+ splice variants of MYPT1.


Assuntos
Círculo Arterial do Cérebro/enzimologia , GMP Cíclico/metabolismo , Artéria Femoral/enzimologia , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Óxido Nítrico/metabolismo , Vasoconstrição , Vasodilatação , Processamento Alternativo , Animais , Círculo Arterial do Cérebro/efeitos dos fármacos , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Artéria Femoral/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatase de Miosina-de-Cadeia-Leve/deficiência , Fosfatase de Miosina-de-Cadeia-Leve/genética , Fosforilação , Sistemas do Segundo Mensageiro , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
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