Arteries are finely tuned thermosensors regulating myogenic tone and blood flow

Abstract

In response to changing blood pressure, arteries adjust their caliber to control blood flow. This vital autoregulatory property, termed vascular myogenic tone, stabilizes downstream capillary pressure. Here, we reveal that tissue temperature, combined with intraluminal pressure, critically determines myogenic tone. Heating steeply activates tone in skeletal muscle, gut, brain, and skin arteries with temperature coefficients (Q₁₀) of ~11 to 20. Each of these tissues has a distinct resting temperature, and we find that arterial thermosensitivity is tuned to this temperature, making myogenic tone sensitive to small thermal fluctuations. Interestingly, temperature and intraluminal pressure are sensed largely independently and the signals integrated to trigger myogenic tone. We demonstrate that thermosensitive channels TRPV1 and TRPM4 mediate heat-induced tone in skeletal muscle arteries with discrete temperature sensitivities. Similarly, TRPM4 contributes to heat-induced tone in gut and brain arteries. The half-maximal responses occur at approximately 31 °C for TRPV1 and 33 °C for TRPM4. Variations in tissue temperature are known to alter blood fluidity and therefore vascular conductance; remarkably, thermosensitive tone counterbalances this effect, thus protecting capillary integrity and fluid balance. In conclusion, thermosensitive myogenic tone is a fundamental homeostatic mechanism regulating tissue perfusion.

Keywords: TRP channels; blood flow; myogenic tone; temperature.

Fig. 1.

Myogenic tone is highly thermosensitive. (A) Representative photographs of pressurized (80 mmHg) skeletal muscle arterioles at different temperatures. (B and C) Changes in the diameter of pressurized (80 mmHg) skeletal muscle arteries in response to an increase or decrease in bath temperature (indicated by red dotted line). PSS: physiological salt solution. (D) Mean myogenic tone (%) versus temperature (Left) and representative Arrhenius plot (Right) yielding indicated Q₁₀ values and threshold temperatures (T) for skeletal muscle arteries (n = 16; Hill fit, r² = 0.893, linear fits r² = 0.986, 0.941). The mean half-maximal temperature for tone (T_1/2) was derived from fits to modified Hill equations of individual arteries. (E) Representative photographs of pressurized (80 mmHg) mesenteric and hairy skin arterioles at different temperatures. (F–I) Mean myogenic tone (%) versus temperature (Left) and representative Arrhenius plots (Right) yielding indicated Q₁₀ values and threshold temperatures (T) for arteries. Plots of (F) mesenteric arteries (n = 16, Hill fit, r² = 0.828, linear fits, r² = 0.986, 0.968), (G) pial arteries (n = 8; Hill fit, r² = 0.884, linear fits, r² = 0.966, 0.887), (H) hairy skin arteries (n = 10; Hill fit, r² = 0.837, linear fits, r² = 0.978, 0.960), and (I) glabrous skin arteries (n = 7; Hill fit, r² = 0.712, linear fits, r² = 0.980, 0.992, 0.982, n.a.). The mean half-maximal temperature for tone (T_1/2) indicated was derived from fits to modified Hill equations of individual arteries.

Fig. 2.

The thermosensitivity of myogenic tone correlates with resting tissue temperature. (A) Illustration of thermal tissue variations in mice. Approximate resting tissue temperatures were obtained from published values for skeletal muscle, brain, gut, hairy skin, and glabrous skin (–49) at an ambient temperature of 21 °C to 22 °C. (B) Plot of myogenic tone T_1/2 for individual arteries from skeletal muscle (n = 14), mesenteric (n = 16), pial (n = 8), hairy skin (n = 10), and glabrous skin (n = 7) versus the resting tissue temperature.

Fig. 3.

Distinct pressure and temperature sensors mediate myogenic tone in skeletal muscle. (A) Myogenic tone versus pressure in a single skeletal muscle arteriole at 32 °C, 35 °C, and 39 °C (Left) and the mean responses of arteries from six animals (Right). (B) Plot of half maximal pressure (P_1/2) versus temperature (n = 5, one-way ANOVA with repeated measures, *P < 0.05, 32 °C versus 39 °C). P_1/2 values were obtained from the data in A. (C and D) Myogenic tone versus temperature, measured at intraluminal pressures of 40, 80, and 120 mmHg and plot of T_1/2 versus pressure (n = 4, one-way ANOVA with repeated measures, ns, 40 versus 80 and 120 mmHg). (E–K) TRPV1 and TRPM4 mediate thermo-tone. (E) Membrane potential in smooth muscle cells of skeletal muscle arteries pressurized to 10 mmHg (n = 25) or 100 mmHg (36 °C, n = 25; 28 °C, n = 19; 35 °C, n = 21; 35 °C plus BCTC, n = 14; one-way ANOVA, **P < 0.01, ***P < 0.001). (F and G) The mean myogenic tone before and after treatment with the TRPV1 antagonist, BCTC (n = 4), and the TRPM4 antagonist, NBA (n = 4) (one-way ANOVA with repeated measures, *P < 0.05, **P < 0.01, PSS versus BCTC/NBA). (H) Plots of BCTC and NBA-subtracted myogenic tone (normalized to peak response) for individual skeletal muscle arteries reveal the pure TRPV1 and TRPM4 components. The smooth lines are fits to a modified Hill equation. (I) The T_1/2 for the TRPV1 component in skeletal muscle arteries (n = 5) and the TRPM4 component in skeletal muscle (n = 3), mesenteric (n = 3), and pial arteries (n = 4) (unpaired t-test **P < 0.01; one-way ANOVA, ns, TRPM4 groups). (J) Thermo-tone in control arteries (PSS) (data replotted from Fig. 1D, T_1/2 = 32.9 °C), and arteries treated with the PLC inhibitor, ET 18-OCH₃ (T_1/2 = 38.5 °C, n = 6). (K) The maximal myogenic tone at 41 °C for control (PSS, n = 10), ET 18-OCH₃ (n = 6), ET 18-OCH₃ + BCTC (n = 6) and ET 18-OCH₃ +NBA (n = 6) (one-way ANOVA, *P < 0.05, ET versus BCTC/NBA, ***P < 0.001, PSS versus all groups).

Fig. 4.

Temperature regulates myogenic tone in vivo. (A) Anesthetized mice were maintained at a core/skeletal muscle temperature (T_C/T_Sk.M) of 32 °C/29 °C or 36 °C/33 °C. (B) Representative systemic blood pressure (BP) and heart rate (HR) recording during i.v. administration of the TRPV1 inhibitor, BCTC (3 mg/kg, dotted line). (C) The change in the mean BP evoked by BCTC at different T_C (32 °C, n = 4; 36°C, n = 6, unpaired t-test, *P < 0.05). (D and E) Summary of mean arterial pressure and heart rate (32 °C n = 4; 36 °C, n = 6; one-way ANOVA, *P < 0.05, **P < 0.01). (F and G) Intravital imaging of mouse radial muscle feed arteriole (green arrow) and veins (yellow arrow) shows arteriole constriction in response to local perfusion of heated PSS (30 °C, 34 °C and 37 °C, one-way ANOVA with repeated measures, n = 5, **P < 0.01, ***P < 0.001).

Fig. 5.

Thermo-tone opposes heat-evoked increases in blood flow. (A) Top, illustration of the intravital imaging field (dotted box) in the mouse forearm. Bottom, expanded view showing the radial muscle branch artery (red arrows) and a vein (yellow arrows). (B) Representative laser speckle contract images show that heating increases perfusion while the artery constricts. (C) Fractional artery diameter versus temperature (n = 8, one-way ANOVA with repeated measures, ***P < 0.001). (D and E) Relative arterial blood perfusion during limb heating from 28 to 41 °C with physiological salt solution (PSS, black) and Ca²⁺ free/sodium nitroprusside PSS (blue) (n = 6, one-way ANOVA, PSS versus Ca²⁻ free **P < 0.01, ***P < 0.001). (F–H) Relative blood perfusion with PSS (black), BCTC+NBA (purple), nifedipine (NIF, green), and Ca²⁺ free/sodium nitroprusside PSS (blue), (n = 9, one-way ANOVA, PSS 28 °C/34 °C/39 °C versus treatment groups, *P < 0.05, **P < 0.01, ***P < 0.001). Note: all media contained the α1 adrenergic inhibitor, prazosin (10 µM).

Fig. 6.

A model for temperature-dependent myogenic tone. (A) A proposed signaling pathway for thermo-tone. Stretch-induced PLC signaling and temperature converge to activate thermo-sensitive ion channels in VSMCs. In turn, membrane depolarization activates voltage-gated Ca²⁺ channels (Ca_V1.2) resulting in raised myoplasmic Ca²⁺ and ultimately leading to the phosphorylation of myosin light chain necessary for contraction. Image constructed using Biorender. (B) Idealized blood flow versus pressure relationship in a skeletal muscle artery (with a fixed temperature of 36 °C) showing myogenic tone (black line) operating between 40 and 150 mmHg. The blue line indicates zero myogenic tone. This relationship is based on a published model (62). (C) Idealized blood flow versus temperature in a skeletal muscle artery (with a fixed pressure of 80 mmHg) showing myogenic tone acting between 30 to 40 °C. This model is based on data in Fig. 5.