Vascular diseases such as atherosclerosis and
restenosis after arterial or transplantation are associated with
remodeling of vascular wall with thickening of the intimal layer.
During the early stages of arterial thickening, vascular smooth
muscle cells undergo transition from a contractile phenotype to a
synthetic phenotype, which is associated with increased production of
extracellular matrix (ECM) proteins, such as osteopontin and
thrombospondin.
Our lab is interested in the role of nitric oxide
(NO)/cGMP signaling in vascular diseases, and specifically the role of
cGMP-dependent protein kinase (PKG) in vascular smooth muscle cell
growth and differentiation. I
have been interested in the role of the NO-cGMP-PKG pathway in
regulating ECM protein expression.
PKG inhibits the expression of osteopontin and thrombospondin by
both transcriptional and posttranscriptional mechanisms.
Recently, I have shown that PKG inhibits the expression of matrix
metalloproteinase 2 (MMP-2) in vascular smooth muscle cells.
Degradation and resynthesis of the extracellular matrix are
essential during vascular tissue remodeling.
Our experimental data may indicate that by inhibiting the
expression of MMP-2, PKG may inhibit neointima formation in response to
arterial tissue and atherosclerosis.
N.J. Boerth, N.B. Dey, T.L.
Cornwell, and T.M. Lincoln. (1997)
Cyclic GMP-dependent protein kinase regulates vascular smooth
muscle cell phenotype. Journal
of Vascular Research, 34:245-259.
N.B. Dey,
N.J. Boerth, J.E. Murphy-Ullrich, P.L. Chang, C.W. Prince, and T.M.
Lincoln. (1998)
Cyclic GMP-dependent protein kinase inhibits osteopontin and
thrombospondin production in rat aortic smooth muscle cells.
Circulation Research,
82:139-146.
T.M. Lincoln, N.B.
Dey, N.J. Boerth, T.L. Cornwell, and G.A. Soff. (1998)
The nitric oxide-cyclic GMP pathway regulates vascular smooth
muscle cell phenotypic modulation:
implication in vascular diseases.
Acta Physiologica
Scandanavia, 164:507-516.
T.M. Lincoln, N.B.
Dey, and H. Sellak. (2001)
cGMP-dependent protein kinase signaling mechanisms in smooth
muscle: from the regulation of tone to gene expression.
Journal of Applied Physiology, 91:1420-1430.
J.P. Stegemann, N.B.
Dey, T.M. Lincoln, and R.M. Nerem.
(2003) Genetic
modification of smooth muscle cells to control phenotype and function in
vascular tissue engineering. Tissue Engineering (in press).
N.B. Dey,
K.F. Foley, W. Dostmann, and T.M. Lincoln.
(2003) Inhibition of
cGMP-dependent kinase reverses phenotypic modulation of vascular smooth
muscle cells. Molecular
Pharmacology (submitted).