Abstract
Vascular diseases affect over 1 billion people worldwide and are highly prevalent among the elderly, due to a progressive deterioration of the structure of vascular cells. Most of our understanding of these age-related cellular changes comes from in vitro studies on human cell lines. Further studies of the mechanisms underlying vascular aging in vivo are needed to provide insight into the pathobiology of age-associated vascular diseases, but are difficult to carry out on vertebrate model organisms. We are studying the effects of aging on the vasculature of the invertebrate chordate, Botryllus schlosseri. This extracorporeal vascular network of Botryllus is transparent and particularly amenable to imaging and manipulation. Here we use a combination of transcriptomics, immunostaining and live-imaging, as well as in vivo pharmacological treatments and regeneration assays to show that morphological, transcriptional, and functional age-associated changes within vascular cells are key hallmarks of aging in B. schlosseri, and occur independent of genotype. We show that age-associated changes in the cytoskeleton and the extracellular matrix reshape vascular cells into a flattened and elongated form and there are major changes in the structure of the basement membrane over time. The vessels narrow, reducing blood flow, and become less responsive to stimuli inducing vascular regression. The extracorporeal vasculature is highly regenerative following injury, and while age does not affect the regeneration potential, newly regenerated vascular cells maintain the same aged phenotype, suggesting that aging of the vasculature is a result of heritable epigenetic changes.
Highlights
While vascular tissues play a major role in organismal aging, they are one of the most challenging to study in vivo: the large and continuous network branches to distinct vascular beds and interacts with myriad tissues and organs
Using a combination of transcriptomics, immunostaining and live-imaging, as well as in vivo pharmacological treatments and regeneration assays, we address several important questions regarding vascular aging in Botryllus: What are the key genes driving aging in Botryllus colonies? What age-related changes occur at the cellular level in vascular cells? What is the effect of age-dependent vessel constriction on vascular cells and blood flow? Does aging have an effect on vascular dynamics?
We demonstrate that over time, aging vascular cells undergo distinct and consistent morphological changes that are inherited by newly formed vascular cells upon growth of new vasculature, either normally, or following stimulation by surgical ablation
Summary
While vascular tissues play a major role in organismal aging, they are one of the most challenging to study in vivo: the large and continuous network branches to distinct vascular beds and interacts with myriad tissues and organs. Vascular tissues are found deep within the animal and are largely inaccessible to optical imaging and experimental manipulation Because of these challenges many studies are performed in vitro using cell cultures that allow for greater control of the environmental conditions and improve reproducibility. Age-Dependent Changes of Vascular Cells in vivo requires that the cell- and tissue-level dynamic changes be followed over the lifespan of an organism, adding another level of complexity (Donato et al, 2015, 2018; Xu et al, 2017; Bersini et al, 2020) We address these challenges using a novel model system which allows us to study vascular aging in vivo: the extracorporeal vasculature of the invertebrate chordate, Botryllus schlosseri
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