Hyperoxia evokes pericyte-mediated capillary constriction

Abstract

Oxygen supplementation is regularly prescribed to patients to treat or prevent hypoxia. However, excess oxygenation can lead to reduced cerebral blood flow (CBF) in healthy subjects and worsen the neurological outcome of critically ill patients. Most studies on the vascular effects of hyperoxia focus on arteries but there is no research on the effects on cerebral capillary pericytes, which are major regulators of CBF. Here, we used bright-field imaging of cerebral capillaries and modeling of CBF to show that hyperoxia (95% superfused O2) led to an increase in intracellular calcium level in pericytes and a significant capillary constriction, sufficient to cause an estimated 25% decrease in CBF. Although hyperoxia is reported to cause vascular smooth muscle cell contraction via generation of reactive oxygen species (ROS), endothelin-1 and 20-HETE, we found that increased cytosolic and mitochondrial ROS levels and endothelin release were not involved in the pericyte-mediated capillary constriction. However, a 20-HETE synthesis blocker greatly reduced the hyperoxia-evoked capillary constriction. Our findings establish pericytes as regulators of CBF in hyperoxia and 20-HETE synthesis as an oxygen sensor in CBF regulation. The results also provide a mechanism by which clinically administered oxygen can lead to a worse neurological outcome.

Capillary-Mitochondrial Oxygen Transport in Muscle: Paradigm Shifts

“…In brain and heart the pericyte-associated constriction is slight and too slow to explain the hyperemia kinetics following contractions onset (c.f. in brain, 208 , 210 , 316 and heart, 211 with skeletal muscle 89 ). Is there really the possibility for unitary capillary control in muscle, or rather, is fine-tuning of Q̇O 2 -V̇O 2 matching achieved by ascending vasodilation that increases terminal arteriole diameter and thus RBC flux to all capillaries in a given capillary module.…”

“…Moreover, even under highly nonphysiological conditions (e.g., capillary PO 2 140 to 700 + mmHg) the extent of the pericyte-associated luminal constriction was extremely small (i.e., ∼20%, 1.2 µm; 210 ∼13%, 211 , 212 ) and thus, whereas it might increase individual capillary resistance, it would not be expected to prevent RBC passage. In response to whisker stimulation in mice, somatosensory cortex capillaries dilated ∼5% to 7% of their 4.4 µm baseline within ∼4 to 10 s 208 —faster than some arterioles and considered, by the authors, to be responsible for 84% of the regional blood flow increase.…”

A tight squeeze: how do we make sense of small changes in microvascular diameter?

“…As reviewed previously, this is due to the presence of deformable blood borne cells (Secomb & Pries, 2013). The relationship between vessel diameter ( d ) and viscosity (η) has previously been described (Hirunpattarasilp et al., 2022) in the diameter range between 3 and 8 μm as being given by $$\frac{A}{{{d^n}}}$$, where A and n are constants, with n = 1.647 giving a reasonable fit to experimental data (for a blood haematocrit of 0.45).…”

“…When integrated, and then normalised by the resistance obtained when the capillary diameter is d 2 everywhere, this produces the following equation (Hirunpattarasilp et al, 2022) for the ratio of the resistance when the pericyte is constricted to that when the diameter is uniform:…”

“…When integrated, and then normalised by the resistance obtained when the capillary diameter is d 2 everywhere, this produces the following equation (Hirunpattarasilp et al., 2022) for the ratio of the resistance when the pericyte is constricted to that when the diameter is uniform: $$$$\begin{eqnarray} {R}_{\mathrm{constricted}}/{R}_{\mathrm{uniform}}&=&\left[1-{\left({d}_{2}/{d}_{1}\right)}^{(3+n)}\right]/\nonumber\\ &&\left[\left(\left({d}_{1}/{d}_{2}\right)-1\right).\left(3+n\right)\right] \end{eqnarray}$$$$…”