The ageing PVN: cardiovascular implications for reduced TRPV4 expression?

Abstract

Several changes in cardiovascular, metabolic and autonomic function associate with ageing and given the increase in the average human lifespan, a greater understanding of age‐related changes in the physiological control of homeostasis is needed. For example, cardiovascular control by the autonomic nervous system is one of the most vulnerable functions in the aging process, however, the underlying mechanisms are not fully understood.The paraventricular nucleus (PVN) of the hypothalamus is an important autonomic control centre in the brain with many homeostatic roles. PVN neurones project directly to the spinal cord and can modulate cardiovascular function via the sympathetic system. Age‐related changes to the PVN remain largely unknown: PVN cell numbers remain unaltered but little is known about changes in the expression profile of the ion channels. It is hypothesised that any changes in PVN ion channels is likely to result in perturbed physiological processes and/or declined cardiovascular function.In this study, we compared the cardiovascular function of younger (3 months) and older (26 months) adult male Wistar rats. We measured the heart rate, blood pressure (BP) and tail blood volume using non‐invasive tail plethysmography. In addition, we determined the gene expression profiles in the PVN with RNA deep sequencing (RNA‐seq). Results are given as mean ± SEM; significances were assessed by one‐way ANOVA or Student’s t‐tests where appropriate.We found no differences in baseline measurements of blood pressure, heart rate or tail blood volume between adult and aged rats (n=6, p>0.05). We found that slightly higher‐than‐thermoneutral temperatures of 34 °C were required to achieve stable readings from the aged animals. In adult rats, intraperitoneal (i.p) administration of the TRPV4 agonist GSK 1016790A (50 μg/kg) resulted in increased blood pressure and tail blood volume (n=6, p<0.05), whereas this response was absent in aged rats.Our RNA‐seq data showed profound differences in the gene profile of the adult PVN compared to the aged PVN. Bioinformatic analysis showed 3.5‐fold decreased expression of TRPV4 (p<0.05) and the most greatly enriched KEGG pathway was the “Neuroactive Ligand Receptor Interaction” pathway (p<0.5×106) including several important homeostatic control receptors and peptides such as tachykinin 3.Our data illustrates that activation of TRPV4 results in increased blood pressure and tail blood volume in adult rodents, and in aged rodents where there is widespread change of receptor expression, this effect is ameliorated. These experiments were conducted in higher than‐thermoneutral temperatures and TRPV4 has known thermoregulatory roles, therefore further experiments are required to understand the relationship between reduced expression of TRPV4 in ageing and the decline in both cardiovascular and thermoregulatory function via the PVN.Support or Funding InformationThis work was funded by the BBSRC and King Abdulaziz University