Metabolic Control of Microvascular Networks: Oxygen Sensing and Beyond

Abstract

The metabolic regulation of blood flow is central to guaranteeing an adequate supply of blood to the tissues and microvascular network stability. It is assumed that vascular reactions to local oxygenation match blood supply to tissue demand via negative-feedback regulation. Low oxygen (O₂) levels evoke vasodilatation, and thus an increase of blood flow and oxygen supply, by increasing (decreasing) the release of vasodilatory (vasoconstricting) metabolic signal substances with decreasing partial pressure of O₂. This review analyses the principles of metabolic vascular control with a focus on the prevailing feedback regulations. We propose the following hypotheses with respect to vessel diameter adaptation. (1) In addition to O₂-dependent signaling, metabolic vascular regulation can be effected by signal substances produced independently of local oxygenation (reflecting the presence of cells) due to the dilution effect. (2) Control of resting vessel tone, and thus perfusion reserve, could be explained by a vascular activity/hypoxia memory. (3) Vasodilator but not vasoconstrictor signaling can prevent shunt perfusion via signal conduction upstream to feeding arterioles. (4) For low perfusion heterogeneity in the steady state, metabolic signaling from the vessel wall or a perivascular tissue sleeve is optimal. (5) For amplification of perfusion during transient increases of tissue demand, red blood cell-derived vasodilators or vasoconstrictors diluted in flowing blood may be relevant.

Coronary microcirculatory pathophysiology: can we afford it to remain a black box?

“…In conditions of increased demand, metabolic signalling is needed to boost blood flow increase. 49,50 The main effects of impaired metabolic signalling would thus be an increase in spatial perfusion heterogeneity in resting state ( Figure 5B , see also Figure 3 ) and a reduced perfusion increase in conditions of increased demand, e.g. during physical exercise.…”

“…Top: metabolic signals for vascular diameter adaptation may be generated by red blood cells (red arrows), by the vessel wall and the perivascular region (blue arrows), and by parenchymal tissue cells (green arrows). 49,50 Bottom: tissue oxygen distribution in the presence of functional metabolic signalling (left) exhibiting a physiological level of heterogeneity and upon compromised metabolic signalling (right) with strongly increased spatial heterogeneity not compatible with normal tissue function.…”

The capillary bed offers the largest hemodynamic resistance to the cortical blood supply

“…[10][11][12] The functional interaction of cerebral hemodynamics, angioarchitecture, and brain cell metabolism is known as the neurovascular unit (NVU). It has been hypothesized that control of the NVU depends on the orientation and arrangement of the microvessels.…”

Treatment of Angina: Where Are We?

“…Another interesting hypothesis relates to the existence of an altered mismatch between metabolic signalling and microvascular adaptation. It is well known that, in a condition of increased oxygen demand, metabolic signalling evokes several mediators able to increase blood flow [77]. In case of a mismatch of this complex signalling chain, the result will be a heterogeneity of spatial perfusion at rest and a reduced vasodilation when the demand increases, i.e., during physical exercise or stress [78].…”