Signaling Mechanisms to Physiological Function: Electrical and Second Messenger Communication in Resistance Arteries
The goal of this thesis was to develop a deeper understanding of electrical and second messenger communication in small resistance arteries, and how these key biological processes influence vascular contractility and blood flow control. To achieve this goal, we pursued three defined objectives. First, we determined why electrical responses initiated in smooth muscle fail to spread to neighboring cells like their endothelial counterparts. A functional assessment complemented by computational modeling revealed that the structural and connectivity properties of vascular cells play a key role in determining how charge moves asymmetrically among vascular cells. As such, certain cell-specific responses will conduct robustly from cell-to-cell while others will not. Second, we examined the nature of electrical communication in arterial networks and how this key biological process impacts on blood flow control. Once again, using a combination of functional experimentation and computational modeling, we observed that vessel length and branching play a role in determining how electrical phenomenon conduct within a network and influence blood flow control. Further, this work re-emphasizes the essential role of the endothelium in electrical communication and how a modest change in this layer’s coupling, due to disease, can compromise network perfusion. Lastly, using an integrated experimental approach, we explored whether second messengers could cross myoendothelial gap junctions and elicit a feedback response that limits constriction. This pathway begins with agonists inducing smooth muscle cell depolarization and a rise in second messenger concentration. Next, IP3 fluxes across myoendothelial gap junctions and elicits inducible Ca2+ wavelets, an event that in turn activates endothelial IK channels. The resulting hyperpolarization then moderates iv the initial depolarization of smooth muscle. Overall, the findings arising from the three objectives shed new light onto the basis of vasomotor and blood flow control in the resistance vasculature.
calcium transients, signal transduction, potassium channels, gap junctions, microcirculation