Defense Date


Document Type


Degree Name

Doctor of Philosophy



First Advisor

Dr. Paul Ratz


The contractile state of vascular smooth muscle (VSM) plays a key role in blood pressure regulation. Abnormal VSM contractility characterizes hypertension and understanding the regulatory mechanisms of VSM may provide some insights to specific treatment of hypertension. Upon muscle stimulation, Ca2+, myosin light chain (MLC) phosphorylation, crossbridge cycling rates and force increase to high levels, but with time, force is maintained while all other parameters of muscle activation fall to low levels. Thus, contraction is divided temporally into early (phasic) and late (tonic) phases, as determined by the underlying regulatory mechanism. Muscles with more phasic characteristics have a higher peak phase while tonic muscles have both high peak and tonic. However, these muscles have similar contractile increases in Ca2+ despite their substantial differences in force production during the tonic phase of contraction. Myosin light chain phosphatase (MLCP) inhibition by RhoA Kinase (ROK) has been shown to contribute to this increased force production without simultaneous increases in calcium in a process known as Ca2+ sensitization.Epigastric artery (EA) has a unique regulatory mechanism controlled by the degree of stretch applied on the artery which produces an increase in tonic force maintenance. Tonic force in EA is blocked equally at all lengths by the ROK inhibitor Y-27632, suggesting ROK is the main mechanism of signal transduction activated.MLC-p is increased during basal compared to unstretched conditions for epigastric but not femoral artery (FA). Pharmacological MT depolymerization due to Colchicine incubation has been shown to release RhoGEF, a RhoA activator, and resulted in increased tonic force and MLC-p which were both inhibited by a ROK inhibitor.Additionally, KC1-stimulation appeared to activate MAPK and ROK pathways, while stretch alone activated a yet undetermined pathway, possibly ILK. KC1-induced contraction in FA activated TRP sensitive calcium channels during both peak and tonic phases. However, stretch in EA does not induce additional calcium influx. Thus, these data support the conclusion that an increase in length activates ROK and other kinases resulting in tonic force maintenance in EA.


© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

June 2008