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Blood flow conditions resistance artery smooth muscle gene expression and vasodilator responses
Author(s) -
Zhang HaiYing,
Fisher Steven A.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a305
Subject(s) - myosin light chain phosphatase , vasodilation , phenylephrine , vascular smooth muscle , medicine , vascular resistance , endocrinology , cgmp dependent protein kinase , myosin , chemistry , protein kinase a , biology , kinase , hemodynamics , myosin light chain kinase , microbiology and biotechnology , blood pressure , smooth muscle , cyclin dependent kinase 2
Inhibition of the myosin phosphatase (MP) by the cGMP‐dependent protein kinase (cGK) is a key step in NO/cGMP‐mediated smooth muscle relaxation. The leucine zipper (LZ) mediated hetero‐dimerization of the MP targeting subunit (MYPT1) with cGK is required for inhibition of MP. We have proposed that expression of MYPT1 LZ+/− isoform variants sets the sensitivity of smooth muscle to NO/cGMP mediated relaxation. We previously showed in a model of portal hypertension (high cardiac output/low vascular resistance) dynamic switching of the MA1 (1 st order mesenteric artery) from MYPT1 LZ‐ to LZ+. We hypothesized that altered blood flow may condition vascular smooth muscle (VSM) and thereby determine vasodilator responses. We adapted the model of DeMey, in which adjacent MA1s are exposed to chronically elevated (HF) or reduced blood flow (LF) by ligation of MA2s (2 nd order MA) of every other MA1. MYPT1 protein was down‐regulated within 1 day of HF and LF conditions to less than 10% of control values along with a switch to the LZ+ isoform. In the HF arteries this was transient, with a switch back to control values by 28 days. In contrast in the LF arteries there was a continued transition to LZ+ isoform along with a return of MYPT1 protein levels at 28 days. Phenylephrine activated LF MA1 was 4‐fold more sensitive to 8Br‐cGMP (EC 50 CTL or HF 3.6±0.9x10 −5 M vs LF 8.4±2.3 × 10 −6 M, P <0.05). We propose that flow conditions the resistance artery VSM, and that changes in MYPT1 expression in response to altered flow functions as a rheostat to set the level of sensitivity of VSM to dilator signals in order to normalize flow rates. Supported by NIH HL66171.