Physiological Basis of Vascular Contractility

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DESCRIPTION (provided by applicant): Hydrodynamic forces are important intrinsic regulators of contractile function for arterial, venous and lymphatic vessels. All 3 vessel types react to changes in transmural pressure and luminal shear stress, but their responses differ dramatically. In response to pressure elevation, arterioles exhibit strong, sustained constrictions; venules transient, weak constrictions; lymphatics increase their rate of phasic contractions, with little or no change in tone. Shear stress inhibits the pressure-induced responses of all three vessels. Additionally, the contractile responses for each vessel type are variable across different regions of the body, according to the prevailing postural hydrostatic gradients. The central hypothesis of this proposal is that inter-vessel and inter-regional differences in vascular transmural pressure significantly influence the heterogeneity of smooth muscle (SM) contractile protein expression and function. To test this hypothesis, we will determine the extent to which the heterogeneity of vessel function, mechanical properties, and protein expression are determined by transmural pressure. Each aim will utilize adjacent arterioles, venules and lymphatics isolated from 4 different regional environments (leg, neck, thorax, abdomen) of the rat in which the vascular transmural pressure gradients vary. Methods include using isolated/cannulated vessels with controlled pressure/flow, vessel segments on wire myographs under force-feedback control, mRNA, protein and myosin ATPase analyses, immunofluorescence confocal microscopy. In each vessel type at each location our aims are to compare: 1) the functional contractile responses to pressure and shear stress relative to the passive mechanical properties of the vessel wall; 2) active length-tension and force-velocity relationships of vascular SM; 3) expression of SM contractile and regulatory protein isoforms relative to myosin ATPase activity. The results will be integrated to obtain a more complete picture of the similarities and differences between vascular SM in these vessels. We predict that inter-vessel and inter-regional differences in vascular mechanics and function will reflect underlying differences in the expression of SM contractile protein isoforms. In addition, the functional behaviors of arterioles, venules and lymphatics are predicted to reflect the magnitudes of their respective transmural pressure gradients. These comparisons have not been made before and will significantly advance our understanding of the basis for the heterogeneity in vascular contractile function.