Role for endothelial cell conduction in ascending vasodilatation and exercise hyperaemia in hamster skeletal muscle.

Ascending vasodilatation entails the progression of smooth muscle relaxation from distal branches of the arteriolar network, through intermediate and proximal arteriolar segments, and into the arterial supply proximal to the muscle (Hilton, 1959; Folkow et al. 1971; Goodman et al. 1978; Williams & Segal, 1993; Welsh & Segal, 1997). This coordinated interaction within and among vascular segments is invoked by a mismatch between oxygen supply and demand during hypoxia (Granger et al. 1976) and by rhythmic contractions of skeletal muscle (Hilton, 1959; Welsh & Segal, 1997; Van Teeffelen & Segal, 2000). Independent of neural pathways (Honig & Frierson, 1976), two distinct mechanisms have been proposed to explain how vasodilatation spreads from intramuscular arterioles into the proximal arterial supply. One mechanism invokes flow-induced vasodilatation, which reflects the increase in luminal shear stress (the product of wall shear rate, WSR, and blood viscosity) acting on endothelial cells to stimulate the production of vasodilatory autacoids (Pohl et al. 1986; Koller & Kaley, 1990; Smiesko & Johnson, 1993; Koller et al. 1994; Davies, 1995). In this manner, dilatation of the distal segments will increase flow through the proximal segments to stimulate endothelial cells. An alternative mechanism entails the production of a dilatory signal that may be conducted from cell to cell along the vessel wall (Segal & Duling, 1986b; Welsh & Segal, 1998; Emerson & Segal, 2000a,b) in response to the contraction of skeletal muscle fibres (Hilton, 1959; Welsh & Segal, 1997). Micropressure measurements indicate that the feed arteries of the hamster retractor muscle (Welsh & Segal, 1996) and of the rat soleus and extensor digitorum longus muscles (Williams & Segal, 1993) contribute up to ∼30 % of the total resistance to blood flow. In these preparations, as well as the rat spinotrapezius muscle (Lash, 1994), dilatation of feed arteries has been observed in response to rhythmic muscle contractions. In the retractor muscle, dilatation of the feed arteries increases with duty cycle (Welsh & Segal, 1997) and with motor unit recruitment (Van Teeffelen & Segal, 2000). Conversely, ascending vasodilatation is suppressed during muscle fatigue and reductions in metabolic demand (Jacobs & Segal, 2000). Indeed, the lack of feed artery dilatation has been predicted to limit muscle blood flow by maintaining high vascular resistance proximal to the arteriolar network (Segal & Duling, 1986a; Williams & Segal, 1993). Remarkably, the signalling mechanism by which vasodilatation originating within exercising skeletal muscle is transmitted upstream into the arterial supply has remained unresolved. In vitro studies of feed arteries from the retractor muscle have demonstrated that the conduction of hyperpolarisation along the endothelial cell layer is highly effective in driving the hyperpolarisation and relaxation of surrounding smooth muscle cells (Emerson & Segal, 2000a,b, 2001). Furthermore, acetylcholine reliably evokes hyperpolarisation of endothelial cells to initiate the conduction of vasodilatation along arterioles as well as feed arteries (Welsh & Segal, 1998; Emerson & Segal, 2000a). Whereas the conduction of vasodilatation into feed arteries has been inferred in studies of functional hyperaemia (Hilton, 1959; Welsh & Segal, 1997), it has not been established whether conduction is actually evoked by muscular activity; nor has the cellular pathway of ascending vasodilatation been ascertained. In the present study, our goal was to determine the mechanism by which vasodilatation ascends from within contracting skeletal muscle and into its feed arteries. We hypothesised that cell-to-cell conduction along the endothelium is a critical component of the integrated vasomotor response. To test this hypothesis, endothelial cells within a segment of a feed artery supplying the retractor muscle were selectively damaged using light-dye treatment (LDT; Bartlett & Segal, 2000; Emerson & Segal, 2000a). Feed artery responses to muscle contraction were evaluated before and after LDT with corresponding reference to the conduction of vasodilatation evoked by acetylcholine. Red blood cell velocity (Vrbc) and luminal diameter were evaluated concomitantly to determine whether changes in blood flow and WSR (a direct index of luminal shear stress assuming constant blood viscosity) were integral to ascending vasodilatation.