Integration of Metabolic Response Pathways

A. Myoendothelial Communication

In addition to considerations about which control mechanisms for arteriolar responses reside on SMCs versus ECs, it has become apparent that these two cell types can be closely coupled, thus enabling the arteriolar wall to act as a syncytium. In small arterioles there are gap junctions between adjacent ECs and between adjacent SMCs; in addition the two cell types are connected by myoendothelial gap junctions. This arrangement allows signals to spread axially along the vessel, and also to be communicated directly between ECs and SMCs. Local paracrine signaling from ECs to SMCs is, of course, well established (NO, EDHF), but it is now clear that intracellular transfer of signaling intermediates can also occur from SMCs to ECs. It has recently been shown that the increased SMC Ca2+ that occurs when arterioles constrict can be transferred to ECs, raising Ca2+ in these cells and contributing to NO release, which in turn ameliorates the original vasoconstriction. How this response pattern contributes to in situ arteriolar responses is not yet clear, but it indicates that vessels in their native environment can respond in an even more closely integrated way than previously thought.

B. Axially Propagated Responses

In the past two decades, a great deal of work, much of it in skeletal muscle arterioles, has established that in these vessels, responses can be propagated axially over considerable distances (millimeters) from their point of local origin. Most of this work has focused on understanding the mechanisms underlying dilations and constrictions conducted axi-ally as a result of local stimulation by acetylcholine and phenylephrine, respectively. These agents induce hyper- and hypopolarizations, respectively, that are transmitted axially along the vessel in a manner that appears to be dependent largely (although not necessarily entirely) on gap-junction communication. Although the principal pathway for this transmission appears to be ECs, signals can also be transmitted via a SMC pathway, and an important task will be to identify what control mechanisms determine whether transmission is via ECs or SMCs or both cell types. Not all local vasomotor events result in a propagated signal; for example, it has been shown that contraction of skeletal muscle fibers causes a local dilation that involves ADO, NO, and a separate, KATP channel-dependent pathway, but that the NO-dependent component of this response is not propagated axially, whereas the ADO and KATP channel-dependent components are. Similarly, locally applied purines induce a mixed response, constriction followed by dilation, but only the dilator component is propagated axially. Not all of these responses appear to depend entirely on gap-junctionally mediated transmission, but what other signaling pathways are involved is not known at this time. Initial work suggests that the remote response to purines is dependent on increased EC Ca2+ at the remote site, but how this relates to the signaling cascade is entirely unknown. Despite the fact that there is much to be learned about the mechanisms underlying these communicated responses, their potential contribution to integration of skeletal muscle responses is clear. If only local dilations were produced in muscles in response to contraction of individual motor units, then at submaximal motor unit recruitment one might expect arteri-oles to exhibit a series of randomly located local dilations that would not support changes in flow through the vessel:

Conduction of these dilations along the arteriolar wall allows the vessel to respond as a coordinated entity, thus facilitating decreased resistance to flow across the vessel (and network region) as a whole.

C. Flow-Dependent Dilations

Skeletal muscle arterioles are sensitive to flow, and, interestingly, larger rather than smaller vessels are more responsive to this stimulus (compared to the conducted responses discussed earlier, which appear to be most prominent in smaller arterioles). It has also been shown that ascending flow-dependent dilations can be propagated proximally to encompass the inflow vessels to the tissue, thus enabling flow to be increased to the entire tissue. Thus the picture that is emerging is one in which small arterioles, by reason of their electrical and/or local paracrine coupling, are able to exhibit responses that are conducted beyond their region of origin to enable the vessel to respond as a coordinated whole, while larger arterioles, being flow sensitive, exhibit an ascending dilatory behavior that subserves increased flow into the tissue under conditions of increased metabolism.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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