Myosin phosphatase isoform switching in vascular smooth muscle development.
We are using the myosin phosphatase targeting subunit (MYPT1) as a model gene to study smooth muscle phenotypic diversity. Myosin phosphatase (MP) is the primary effector of smooth muscle relaxation, and MYPT1 is a key target of signals that regulate smooth muscle tone. In a model of portal hypertension we previously showed dynamic changes in the expression of MYPT1 isoforms in the portal vein and upstream mesenteric artery. We hypothesized that this represents a reversion to the fetal phenotype characteristic of muscle hypertrophy. Here we studied MP during vascular smooth muscle phenotypic specification. Between postnatal days 6 and 12 the expression of MYPT1 increased approximately twofold in portal vein with a similar increase in MP activity. MYPT1 switched from C-terminal leucine zipper (LZ) positive to LZ negative splice variant isoforms. This was concordant with a switch from sensitive (10(-7) M) to resistant to cGMP-mediated vascular relaxation. This is consistent with the model in which the MYPT1 C-terminal LZ is required for cGMP-dependent activation of MP. Concordant changes in the expression of other contractile proteins were consistent with a switch from a slow-tonic to a fast-phasic contractile phenotype. In contrast aortic smooth muscle throughout development expressed the MYPT1 LZ positive isoform and relaxed to cGMP. We propose that MP isoform switching during neonatal vascular smooth muscle phenotypic specification may determine changing vascular responses to NO/cGMP signaling in the transition from the fetal to the adult circulation.
Payne
Michael C
MC
Department of Medicine, 422 BRB, 2109 Adelbert Road, Case Western Reserve School of Medicine, Cleveland, OH 44106-4958, USA.
Zhang
Hai-Ying
HY
Prosdocimo
Tony
T
Joyce
Katherine M
KM
Koga
Yasuhiko
Y
Ikebe
Mitsuo
M
Fisher
Steven A
SA
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D006152:Cyclic GMP / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000196:embryology* / Q000201:enzymology*; D043263:Myosin-Light-Chain Phosphatase / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics
D007527:Isoenzymes; D009124:Muscle Proteins; D010455:Peptides; D010750:Phosphoproteins; C491519:Ppp1r14a protein, rat; C065738:MLCK peptide; D017869:Cyclic GMP-Dependent Protein Kinases; D043263:Myosin-Light-Chain Phosphatase; D020742:rhoA GTP-Binding Protein; D006152:Cyclic GMP