Fluid mechanical forces generated by blood flow alter the metabolism of endothelium that line the blood vessel. In 1989, Scott Diamond published in Science an observation that fluid shear stress, instead of a biochemical signal, could control the genetic program of a living cell. The Diamond laboratory proceeded to identify the molecular mechanisms of cellular adaptation and dysfunction in mechanical environments. Mechanical deformations cause endothelial cell calcium mobilization (a regulator of metabolism) and that fluid shear increases endothelial c-fos protein (a regulator of gene transcription). Also, the production of the two most potent vasodilators, nitric oxide (NO) and prostacyclin, is highly coupled during mechanical force induction. In fact, high levels of shear stress shut down gene expression of the potent vasoconstrictor, endothelin, while the vasodilatory genes, eNOS and CNP, are upregulated. Finally, Diamond solved a 150-year old paradox in cardiovascular fluid dynamics called “poststenotic dilatation” where arteries hyperdilate downstream of a narrowing. Diamond discovered that NO is the mediator of this hydrodynamic maladaptation.
Currently, it remains unknown by what mechanisms exercise and gender lead to protection of the blood vessels. Our lab has recently discovered (Circulation Res., 2003) that fluid mechanical forces can actually act like the anti-inflammatory steroids(dexamethasone). Fluid shear stress activates the glucocorticoid receptor and turns on genes that contain glucocorticoid response elements in their promoter.
S. L. Diamond, S. G. Eskin, and L. V. McIntire, "Fluid Flow Stimulates Tissue Plasminogen Activator Secretion by Cultured Human Endothelial Cells," Science 243, 1483 (1989).
J. B. Sharefkin, S. L Diamond, C. W. Dieffenbach, and S. G. Eskin. "Effects of Sustained Laminar Shear Stress on Tissue Plasminogen Activator Levels," In: Cardiovascular Science and Technology (J. Norman, editor) Oxymoron Press, Louisville, p. 81 (1989).
S. L. Diamond, J. B. Sharefkin, S. G. Eskin, C. Dieffenbach, K. Frasier-Scott, and L. V. McIntire, "Tissue Plasminogen Activator Messenger RNA Levels Increase in Cultured Human Endothelial Cells Exposed to Laminar Shear Stress," J. Cell. Physiol. 143, 364 (1990).
J. B. Sharefkin, S. L. Diamond, S. G. Eskin, C. Dieffenbach, and L. V. McIntire, "Fluid Flow Decreases Endothelin mRNA Levels and Suppresses Endothelin Peptide Release in Human Endothelial Cells," J. Vasc. Surg. 14, 1 (1991).
S. L.Diamond, J. B.Sharefkin, C. W. Dieffenbach, S. G.Eskin, and L. V. McIntire, "Regulation of Endothelial Cell Gene Expression by Hemodynamic Forces: Implications for Intimal Hyperplasia and Graft Patency," In: Technologies in Vascular Surgery, W. B. Saunders, Philadelphia (J. S. T. Yao and W. H. Pearce, eds.) p. 12-24 (1991).
M. U. Nollert, S. L. Diamond, and L. V. McIntire, "Hydrodynamic Shear Stress and Mass Transport Modulation of Endothelial Cell Metabolism," Biotech. Bioengr. 38, 588 (1991).
W. Sigurdson, F. Sachs, and S. L. Diamond, "Mechanical Perturbation of Cultured Human Endothelial Cells Causes Rapid Increases of Intracellular Calcium." Amer. J. Physiology 264, H1745 (1993).
M.Yamaguchi, S. L. Diamond, H. Watanabe, H. Gallati, W. Baur, and J. B. Sharefkin. Heparin and Dibutyryl cAMP Modulate Gene Expression in Stimulated Human Saphenous Vein Smooth Muscle Cells. In Vitro Cell. Devel. Biol. 29, 863 (1993).
V. Ranjan and S. L. Diamond, "Fluid Shear Stress Induces Synthesis and Nuclear Localization of c-Fos in Cultured Human Endothelial Cells," Biochem. Biophys. Res. Comm. 196, 79 (1993).
S. L. Diamond, F. Sachs, and W. J. Sigurdson. "The Mechanically-Induced Calcium Mobilization in Cultured Endothelial Cells is Dependent on Actin and Phospholipase," Arteriosclerosis Thrombosis 14, 2000 (1994).
S. L. Diamond and L. V. McIntire, "Gene Regulation in Endothelial Cells," In: Flow Dependent Regulation of Vascular Function in Health and Disease," Oxford University Press, New York (J. A. Beven, G. Kaley, G. M. Rubanyi, eds.) Chapter 4. p. 62-84 (1995).
V. Ranjan, S. Z. Xiao, and S. L. Diamond. "Constitutive NOS Expression in Cultured Endothelial Cells is Elevated by Fluid Shear Stress." Amer. J. Physiol. 268, H550 (1995).
V. Ranjan, R. Waterbury, and S. L. Diamond. "Fluid Shear Stress Induction of the Transcriptional Activator c-fos in Human and Bovine Endothelial Cells, HeLa, and CHO Cells." Biotech. Bioeng. 49, 383 (1996).
Z. Xiao, X. Zhang, S.L. Diamond. "Shear stress induction of endothelial nitric oxide synthase is calcium-dependent, but not calcium-activated." J. Cell. Physiol. 171, 205 (1997).
W. Wang, S.L. Diamond. Does elevated nitric oxide production enhance the release of prostacyclin from shear stressed aortic endothelial cells? Biochem. Biophys. Res. Comm. 233, 748 (1997).
W. J. Calvo, G. Hajduczok, J.A. Russell, and S.L. Diamond. "Inhibition of nitric oxide but not prostacyclin prevents poststenotic dilatation in rabbit femoral artery." Circulation. 99, 1069 (1999).
Z. Zhang, Z. Ziao, and S. L. Diamond. "Shear stress induction of C-type natriuretic peptide (CNP) in endothelial cells is independent of NO autocrine signaling" Annals Biomed. Engr. 27, 419 (1999).
S. L. Diamond. "Intracellular Receptors--Steroid Receptors and Nitric Oxide." Animal Plant Cell Tech. 7, 1097 (2000).
J. Y. Ji, H. Jing, S. L. Diamond. Shear stress enhances nuclear localization of endothelial glucocorticoid receptor and expression from the GRE promoter. Circ. Res. 92, 279 (2003).
J. Ji, S. L. Diamond. Exogenous nitric oxide activates the endothelial glucocorticoid receptor. Biochem. Biophys. Res. Comm. 318:192 (2004).
Ji JY, Jing H, Diamond SL. Hemodynamic regulation of inflammation at the endothelial-neutrophil interface.
Ann Biomed Eng. 2008 Apr;36(4):586-95. Epub 2008 Feb 26.
Pagano N, Wong EY, Breiding T, Liu H, Wilbuer A, Bregman H, Shen Q, Diamond SL, and Meggers E. From Imide to Lactam Metallo-Pyridocarbazoles: Distinct Scaffolds for the Design of Selective Protein Kinase Inhibitors. J Org Chem. 2009 Dec 4;74(23):8997-9009.