Myogenic behavior, prevalent in resistance arteries and arterioles, involves arterial constriction in response to intravascular pressure. This process is often studied in vitro by using cannulated, pressurized arterial segments from different regional circulations. We propose a comprehensive model for myogenicity that consists of three interrelated but dissociable phases: 1) the initial development of myogenic tone (MT), 2) myogenic reactivity to subsequent changes in pressure (MR), and 3) forced dilatation at high transmural pressures (FD). The three phases span the physiological range of transmural pressures (e.g., MT, 40-60 mmHg; MR, 60-140 mmHg; FD, >140 mmHg in cerebral arteries) and are characterized by distinct changes in cytosolic calcium ([Ca(2+)](i)), which do not parallel arterial diameter or wall tension, and therefore suggest the existence of additional regulatory mechanisms. Specifically, the development of MT is accompanied by a substantial (200%) elevation in [Ca(2+)](i) and a reduction in lumen diameter and wall tension, whereas MR is associated with relatively small [Ca(2+)](i) increments (<20% over the entire pressure range) despite considerable increases in wall tension and force production but little or no change in diameter. FD is characterized by a significant additional elevation in [Ca(2+)](i) (>50%), complete loss of force production, and a rapid increase in wall tension. The utility of this model is that it provides a framework for comparing myogenic behavior of vessels of different size and anatomic origin and for investigating the underlying cellular mechanisms that govern vascular smooth muscle mechanotransduction and contribute to the regulation of peripheral resistance.
Abstract-To study endothelial cell (EC)-specific Ca 2ϩ signaling in vivo we engineered transgenic mice in which the Ca 2ϩ sensor GCaMP2 is placed under control of endogenous connexin40 (Cx40) transcription regulatory elements within a bacterial artificial chromosome (BAC), resulting in high sensor expression in arterial ECs, atrial myocytes, and cardiac Purkinje fibers. High signal/noise Ca 2ϩ signals were obtained in Cx40 BAC -GCaMP2 mice within the ventricular Purkinje cell network in vitro and in ECs of cremaster muscle arterioles in vivo. Microiontophoresis of acetylcholine (ACh) onto arterioles triggered a transient increase in EC Ca 2ϩ fluorescence that propagated along the arteriole with an initial velocity of Ϸ116 m/s (nϭ28) and decayed over distances up to 974 m. The local rise in EC Ca 2ϩ was followed (delay, 830Ϯ60 ms; nϭ8) by vasodilation that conducted rapidly (mm/s), bidirectionally, and into branches for distances exceeding 1 mm. At intermediate distances (300 to 600 m), rapidly-conducted vasodilation occurred without changing EC Ca 2ϩ , and additional dilation occurred after arrival of a Ca 2ϩ wave. In contrast, focal delivery of sodium nitroprusside evoked similar local dilations without Ca 2ϩ signaling or conduction. We conclude that in vivo responses to ACh in arterioles consists of 2 phases: (1) a rapidly-conducted vasodilation initiated by a local rise in EC Ca 2ϩ but independent of EC Ca 2ϩ signaling at remote sites; and (2) a slower complementary dilation associated with a Ca 2ϩ wave that propagates along the endothelium. 2ϩ signaling is implicated in regulating the resistance microvasculature. [1][2][3][4][5] Conducted electrical signals travel for millimeters along the vessel wall, 6 mediate coordinated vasomotor responses to localized stimuli, 7-9 and involve distinct Ca 2ϩ signals within smooth muscle (SM) and ECs. For example, arteriolar dilation in response to the endothelium-dependent vasodilator acetylcholine (ACh) involves an increase in ECs 2 and decrease in SM 10 Ca 2ϩ . Although recent intravital studies have demonstrated a crucial role for the endothelium in conducted vasodilation, 9 the extent to which Ca 2ϩ signals are transmitted along the arteriolar wall and the mechanisms underlying Ca 2ϩ transmission are controversial. Some studies indicate that EC Ca 2ϩ responses to dilatory stimuli are localized, 1,2 whereas others indicate that Ca 2ϩ signals can travel along the endothelium for a millimeter or more. 5,11 The majority of information concerning microvascular Ca 2ϩ signaling has been derived from isolated vessels studied in vitro, 4,5,12 largely because of the difficulty of selectively loading ECs or SM cells with Ca 2ϩ sensitive dyes in vivo. 1,10 A fundamental limitation to isolated arterioles is their disconnection from networks in which they normally reside. The extent to which manipulation of arterioles to obtain dye loading and the loss of physiological parameters (eg, pressure or flow) alter Ca 2ϩ signaling is unknown. Therefore, alternative approaches are necessa...
Intracellular calcium concentration ([Ca2+]i) governs the contractile status of arteriolar smooth muscle cells (SMC). Although studied in vitro, little is known of SMC [Ca2+]i dynamics during the local control of blood flow. We tested the hypothesis that the rise and fall of SMC [Ca2+]i underlies arteriolar constriction and dilation in vivo. Aparenchymal segments of second-order arterioles (diameter 35 +/- 2 microm) were prepared in the superfused cheek pouch of anesthetized hamsters (n = 18) and perifused with the ratiometric dye fura PE-3 (AM) to load SMC (1 microM, 20 min). Resting SMC [Ca2+]i was 406 +/- 37 nM. Elevating superfusate O2 from 0 to 21% produced constriction (11 +/- 2 microm) that was unaffected by dye loading; [Ca2+]i increased by 108 +/- 53 nM (n = 6, P < 0.05). Cycling of [Ca2+]i during vasomotion (amplitude, 150 +/- 53 nM; n = 4) preceded corresponding diameter changes (7 +/- 1 microm) by approximately 2 s. Microiontophoresis (1 microm pipette tip; 1 microA, 1 s) of phenylephrine (PE) transiently increased [Ca2+]i by 479 +/- 64 nM (n = 8, P < 0.05) with constriction (26 +/- 3 microm). Flushing blood from the lumen with saline increased fluorescence at 510 nm by approximately 45% during excitation at both 340 and 380 nm with no difference in resting [Ca2+]i, diameter or respective responses to PE (n = 7). Acetylcholine microiontophoresis (1 microA, 1 s) transiently reduced resting SMC [Ca2+]i by 131 +/- 21 nM (n = 6, P < 0.05) with vasodilation (17 +/- 1 microm). Superfusion of sodium nitroprusside (10 microM) transiently reduced SMC [Ca2+]i by 124 +/- 18 nM (n = 6, P < 0.05), whereas dilation (23 +/- 5 microm) was sustained. Resolution of arteriolar SMC [Ca2+]i in vivo discriminates key signaling events that govern the local control of tissue blood flow.
Brekke, Johan Fredrik, Natalia I. Gokina, and George Osol. Vascular smooth muscle cell stress as a determinant of cerebral artery myogenic tone. Am J Physiol Heart Circ Physiol 283: H2210-H2216, 2002; 10.1152/ajpheart. 00633.2002.-Although the level of myogenic tone (MT) varies considerably from vessel to vessel, the regulatory mechanisms through which the actual diameter set point is determined are not known. We hypothesized that a unifying principle may be the equalization of active force at the contractile filament level, which would be reflected in a normalization of wall stress or, more specifically, media stress. Branched segments of rat cerebral arteries ranging from Ͻ50 m to Ͼ200 m in diameter were cannulated and held at 60 mmHg with the objectives of: 1) evaluating the relationship between arterial diameter and the extent of myogenic tone, 2) determining whether differences in MT correlate with changes in cytosolic calcium ([Ca 2ϩ ]i), and 3) testing the hypothesis that a normalization of wall or media stress occurs during the process of tone development. The level of MT increased significantly as vessel size decreased. At 60 mmHg, vascular smooth muscle [Ca 2ϩ ]i concentrations were similar in all vessels studied (averaging 230 Ϯ 9.2 nM) and not correlated with vessel size or the extent of tone. Wall tension increased with increasing arterial size, but wall stress and media stress were similar in large versus small arteries. Media stress, in particular, was quite uniform in all vessels studied. Both morphological and calcium data support the concept of equalization of media stress (and, hence, vascular smooth muscle cell stress and force) as an underlying mechanism in determining the level of tone present in any particular vessel. The equalization of active (vascular smooth muscle cell) stress may thus explain differences in MT observed in the different-sized vessels constituting the arterial network and provide a link between arterial structure and function, in both short-and long-term (hypertension) pressure adaptation.arteries; pressure; wall stress; media stress; intracellular calcium MYOGENIC TONE (MT) is defined as an intrinsic response of vascular smooth muscle (VSM) to transmural pressure or stretch (7,18). This physiological property is well developed in the cerebral circulation and contributes to cerebrovascular resistance and cerebral blood flow autoregulation (15).MT is often studied in vitro by using isolated, pressurized vessel segments in which other confounding influences (e.g., neural, metabolic, and humoral) are absent (4-6, 8, 9, 14). Although the extent of pressureinduced MT varies from vessel to vessel, the principal mechanism underlying tone development in arteries from a number of regional circulations involves VSM membrane depolarization and calcium influx through L-type voltage-gated calcium channels (8). The mechanism by which the level of pressure-induced tone is "set" by a particular vessel, however, is not known. Previous studies have shown that wall stress (1, 13) is ...
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