Blunted temporal activity of microvascular perfusion heterogeneity in metabolic syndrome: a new attractor for peripheral vascular disease?

Abstract

A key clinical outcome for peripheral vascular disease (PVD) in patients is a progressive decay in skeletal muscle performance and its ability to resist fatigue with elevated metabolic demand. We have demonstrated that PVD in obese Zucker rats (OZR) is partially due to increased perfusion distribution heterogeneity at successive microvascular bifurcations within skeletal muscle. As this increased heterogeneity (γ) is longitudinally present in the network, its cumulative impact is a more heterogeneous distribution of perfusion between terminal arterioles than normal, causing greater regional tissue ischemia. To minimize this negative outcome, a likely compensatory mechanism against an increased γ should be an increased temporal switching at arteriolar bifurcations to minimize downstream perfusion deficits. Using in situ cremaster muscle, we determined that temporal activity (the cumulative sum of absolute differences between successive values of γ, taken every 20 s) was lower in OZR than in control animals, and this difference was present in both proximal (1A-2A) and distal (3A-4A) arteriolar bifurcations. Although adrenoreceptor blockade (phentolamine) improved temporal activity in 1A-2A arteriolar bifurcations in OZR, this was without impact in the distal microcirculation, where only interventions against oxidant stress (Tempol) and thromboxane A(2) activity (SQ-29548) were effective. Analysis of the attractor for γ indicated that it was not only elevated in OZR but also exhibited severe reductions in range, suggesting that the ability of the microcirculation to respond to any challenge is highly restricted and may represent the major contributor to the manifestation of poor muscle performance at this age in OZR.

Fig. 1.

Schematic representation of an arteriolar bifurcation used for study. Presented are the key measured parameters of arteriolar diameter and erythrocyte velocity, which are used to calculate blood flow volumes. Perfusion distribution volumes are given as the proportionality parameter γ and (1-γ) in the two daughter arterioles arising from a parent. RBC, red blood cell.

Fig. 2.

Frequency distribution and representative sample of the temporal changes in γ in 1A-2A (A and B, respectively) and 3A-4A (C and D, respectively) arteriolar bifurcations in lean Zucker rats (LZR) and obese Zucker rats (OZR) under control conditions. For data in B and D, γ is determined every 20 s throughout a 5-min collection window.

Fig. 3.

The average γ in 1A-2A arteriolar bifurcations of LZR (A) and OZR (B) over the 5-min collection period. Data (presented as means ± SE) are presented for LZR and OZR under control conditions and in OZR after treatment of the cremaster muscle with phentolamine (Phent), Tempol (Tem), SQ-29548, or combinations of these agents. *P < 0.05 vs. control in that strain.

Fig. 4.

Data describing the cumulative changes in γ over the 5-min collection period in 1A-2A arteriolar bifurcations in LZR and OZR. Data (presented as means ± SE) are presented for LZR and OZR under control conditions and in OZR after treatment of the cremaster muscle with phentolamine (Phent), Tempol (Tem), SQ-29548, or combinations of these agents. Cumulative changes in γ are summated either as differences between successive time points (A and B) or as the absolute differences between successive time points (C and D). *P < 0.05 vs. control in that strain; †P < 0.05 vs. LZR control.

Fig. 5.

The average γ in 3A-4A arteriolar bifurcations of LZR (A) and OZR (B) over the 5-min collection period. Data (presented as means ± SE) are presented for LZR and OZR under control conditions and in OZR after treatment of the cremaster muscle with phentolamine (Phent), Tempol (Tem), SQ-29548, or combinations of these agents. *P < 0.05 vs. control in that strain.

Fig. 6.

Data describing the cumulative changes in γ over the 5-min collection period in 3A-4A arteriolar bifurcations in LZR and OZR. Data (presented as means ± SE) are presented for LZR and OZR under control conditions and in OZR after treatment of the cremaster muscle with phentolamine (Phent), Tempol (Tem), SQ-29548, or combinations of these agents. Cumulative changes in γ are summated either as differences between successive time points (A and B) or as the absolute differences between successive time points (C and D). *P < 0.05 vs. control in that strain; †P < 0.05 vs. LZR control.

Fig. 7.

Data describing the changes in γ over the 5-min collection window in proximal and distal arteriolar bifurcations of LZR and OZR in response to increasing concentrations of adenosine. Data (presented as means ± SE) are presented for 1A-2A arteriolar bifurcations either as average γ (A) or as the cumulative changes in γ, summated as absolute differences (B). Similarly, data for 3A-4A arteriolar bifurcations are presented as average γ (C) or as the cumulative changes in γ, summated as absolute differences (D). *P < 0.05 vs. LZR under that condition; †P < 0.05 vs. LZR control.

Fig. 8.

The effectiveness of the employed interventions at restoring normal activity of γ (cumulative, absolute) at 1A-2A (A) and 3A-4A (B) bifurcations in OZR. Normal activity is defined as that determined in arteriolar bifurcations at those 2 sites in LZR. Data (presented as means ± SE) are presented for OZR after treatment of the cremaster muscle with phentolamine (Phent), Tempol (Tem), SQ-29548, or combinations of these agents. *P < 0.05 vs. no change under that condition.

Fig. 9.

Presentation of the attractor describing the overall spatial-temporal behavior of γ at 1A-2A arteriolar bifurcations in LZR (blue) and OZR (red) under control conditions (A). The attractors are presented as iterated maps, where the respective value for γ is presented at multiple successive time points within that condition. In subsequent panels, the control data are grayed (light for LZR, dark for OZR) and the effects of the interventions on the attractor are presented in black. This is done for treatment with phentolamine (B), Tempol and/or SQ-29548 (C) and phentolamine and Tempol and/or SQ-29548 (D).

Fig. 10.

Presentation of the attractor describing the overall spatial-temporal behavior of γ at 3A-4A arteriolar bifurcations in LZR (blue) and OZR (red) under control conditions (A). The attractors are presented as iterated maps, where the respective value for γ is presented at multiple successive time points within that condition. In subsequent panels, the control data are grayed (light for LZR, dark for OZR) and the effects of the interventions on the attractor are presented in black. This is done for treatment with phentolamine (B), Tempol and/or SQ-29548 (C) and phentolamine and Tempol and/or SQ-29548 (D).

Fig. 11.

Presentation of the attractor describing the overall spatial-temporal behavior of γ at 1A-2A (A) and 3A-4A (B) arteriolar bifurcations in LZR and OZR under control conditions and in response to treatment with 10⁻³ M adenosine. As described in Figs. 9 and 10, the control data are grayed (light for LZR, dark for OZR) and the effects of the elevated adenosine concentration γ in bifurcations in OZR are presented in black.