Haemodynamics and endothelial phenotype heterogeneity
Seminar Room 1, Newton Institute
Endothelial phenotype defines the multi-functional capabilities of the tissue (endothelial monolayer). Within coronary arteries and heart valves, as elsewhere in the arterial circulation, the endothelial phenotype is spatially heterogeneous. Endothelial heterogeneity in general can be considered at different length scales from vascular beds to specialized vascular structures such as heart valves to single cells and it arises from a combination of 'intrinsic' genetic programming and functional changes modified by epigenetic, including important environmental, influences.
A prominent environmental influence is haemodynamics, the usually complex blood flow characteristics that arise from a combination of pulsatile flow, the composition of blood elements, and the geometry of the vessels. Local changes of haemodynamics characteristics, including the flow velocity, direction, frequency and oscillatory behaviour, create two broad consequences in modifying endothelial structure and function. First the transport characteristics of (i) molecules derived from the cells themselves (e.g. short-lived regulatory molecules such as vasoregulators) and (ii) blood molecules that are modified or degraded at the endothelial surface. The kinetics of these solutes is greatly influenced by changes in their transport characteristics in the boundary layer near the cell surface. Second, haemodynamic forces generated by flow, particularly shear stress, greatly influence endothelial biology (and pathophysiology); consequently the steady state phenotype of endothelial cells is sensitive to the temporal-spatial distribution of the forces.
Together, the complex environment defines regions (and perhaps cellular foci) of endothelial phenotypes, with consequences for the underlying artery wall. These mechanisms and their heterogeneous distribution are relevant to the incorporation of vascular biology contributions to the cardiac physiome. I will discuss some of the flow-related mechanisms responsible for endothelial heterogeneity in coronary arteries and valves gathered from genomics, molecular biochemistry and fluid dynamic experimentation, and interpret their pathological implications.
Background References: Davies PF. Flow-mediated endothelial mechanotransduction. Physiol. Rev. 1995, 75:519-560. Davies PF. Polacek, D.C., Shi, C., Helmke, B.P. The Convergence of Hemodynamics, Genomics, and Endothelial Structure, in Studies of the Focal Origin of Atherosclerosis. Biorheology 2002, 39: 299-306. Simmons, C.A, Manduchi, E., Grant, G., Davies, P.F. 2005. Spatial heterogeneity of endothelial phenotypes correlates with side-specific vulnerability to calcification in normal porcine aortic valves. Circ. Research 96:792-799. Davies, P.F. Hemodynamic Shear Stress and the Endothelium in Cardiovascular Pathophysiology. Nature Clinical Practice Cardiovasc. Medicine 2009, 6:16-26.