Abstract
Cerebral arterial vasoreactivity is vital to the regulation of cerebral blood flow. Depolarization of arterial myocytes elicits whole-cell Ca2+ oscillations as well as subcellular Ca2+ sparks due to activation of ryanodine receptors on the sarcoplasmic reticulum. Previous evidence illustrates that contraction of cerebral arteries from sheep and underlying Ca2+ signaling pathways are modified by age and that long-term hypoxia (LTH) causes aberrations in Ca2+ signaling pathways and downstream effectors impacting vasoregulation. We hypothesize that age and LTH affect the influence of membrane depolarization on whole-cell intracellular Ca2+ oscillations and sub-cellular Ca2+ spark activity in cerebral arteries. To test this hypothesis, we examined Ca2+ oscillatory and spark activities using confocal fluorescence imaging techniques of Fluo-4 loaded basilar arterial myocytes of low- and high-altitude term fetal (∼145 days of gestation) and adult sheep, where high-altitude pregnant and non-pregnant sheep were placed at 3,801 m for >100 days. Ca2+ oscillations and sparks were recorded using an in situ preparation evaluated in the absence or presence of 30 mM K+ (30K) to depolarize myocytes. Myocytes from adult animals tended to have a lower basal rate of whole-cell Ca2+ oscillatory activity and 30K increased the activity within cells. LTH decreased the ability of myocytes to respond to depolarization independent of age. These observations illustrate that both altitude and age play a role in affecting whole-cell and localized Ca2+ signaling, which are important to arterial vasoreactivity and cerebral blood flow.
Highlights
In an age where cardiovascular health is so heavily scrutinized, we still struggle to reduce deaths from cardiovascular diseases
The first series of studies were designed to test the hypotheses that membrane depolarization would increase Ca2+ oscillatory activity and that long-term hypoxia (LTH) would impair oscillatory events in basilar arterial myocytes
The current study was designed to examine the impact of animal age and high altitude induced LTH on cytosolic Ca2+ oscillations and sparks in basilar arterial myocytes
Summary
In an age where cardiovascular health is so heavily scrutinized, we still struggle to reduce deaths from cardiovascular diseases. Previous research illustrates that many cardiovascular diseases have origins in fetal development and that gestational stressors have complex effects and impacts on vascular health (Ducsay et al, 2018). There are correlations between brain blood flow, developmental neuropathies, and impaired learning in children as well as psychological disorders such as clinical depression (Koenigs and Grafman, 2009) and dementia (Roher et al, 2012). These interrelationships illustrate the importance of considering the role of dysregulated vessel structure and function in neurological disorders
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