A biomimetic shock model on the effect of endothelial aging on vascular barrier properties

Abstract

BACKGROUND:Aging is characterized by a decline in cellular function, which has an adverse effect on the biologic response to injury. Both aging and trauma/ hemorrhagic shock (T/HS) increase oxidative stress which impairs the vascular endothelium (EC) and glycocalyx (EG). The additive effect of aging on EC and EG damage following T/HS are unknown. This was studied in an in vitro model. METHODS:Confluent endothelial cell monolayers from primary aortic endothelial cells from 10-week-old mice ("young" cells) or primary aortic cells from 65-week-old mice ("aged" cells) were established in microfluidic devices (MFDs) and perfused at constant shear conditions overnight.Mouse endothelial cell monolayers were then exposed to hypoxia/reoxygenation alone and/or epinephrine or norepinephrine. Endothelial glycocalyx degradation was indexed as well as subsequent endothelial injury/activation. RESULTS:Aged endothelial cells showed increase glycocalyx shedding and subsequent loss of glycocalyx thickness. This lead to a more pronounced level of EC injury/activation compared with young endothelial cells. Although exposure to biomimetic shock conditions exacerbated both endothelial glycocalyx shedding and endothelial injury in both aged and young endothelial cells, the effect was significantly more pronounced in aged cells. CONCLUSION: Advanced age is associated with worse outcomes in severely injured trauma patients. Our study demonstrates that there is increased EG shedding and a diminished EG layer in aged compared to "young" endothelial cell layers. Biomimetic shock conditions lead to an even greater impairment of the endothelial glycocalyx in aged versus young endothelial cell monolayers. It appears that these effects are a consequence of aging related oxidative stress at both baseline and shock conditions. This exacerbates shock-induced endotheliopathy and may contribute to untoward effects on patient outcomes in this population.

Endothelial Glycocalyx in Aging and Age-related Diseases

“…EG is the main functional barrier to the vascular endothelium and plays an important role in maintaining selective vascular permeability [ 137 ]. Decreased microvascular density and loss of EG have been found during the aging process [ 51 ]. It has been shown in previous experiments that EG deficiency is closely linked to age-related diseases, thus protecting and repairing the EG is essential for healthy aging.…”

“…Similarly, SA is degraded from erythrocyte membranes at a higher rate in older adults compared to young adults, which may be associated with the increase in oxidative stress during aging [ 50 ]. In vitro study also has shown that aged cells have increased EG shedding and decreased EG layers, and under biomimetic shock conditions, EG shedding is further exacerbated in aged as compared to young endothelial cells [ 51 ]. Human brain is one of the two most abundant tissue sources of KS, and KS has neuroregulatory properties [ 52 , 53 ].…”

SHock-INduced Endotheliopathy (SHINE): A mechanistic justification for viscoelastography-guided resuscitation of traumatic and non-traumatic shock

“…Likewise, early use of VHAs in SIC enables early detection of the depth and duration of shock prior to coagulopathic manifestation by conventional coagulation tests (CCTs) and other standard clinical and biologic markers (Pavoni et al, 2020). Combined with CCTs, VHAs, and clinical and laboratory markers such as lactate and procalcitonin, a PBM approach to assess the depth and duration of shock is becoming a reality whether in TIC or SIC (Vorweg et al, 2013;Müller et al, 2014;Saraiva et al, 2016;Johansson et al, 2017a;Martínez et al, 2018;Stettler et al, 2019;Walsh et al, 2020b;Scarlatescu et al, 2020;Carge et al, 2021;Drost et al, 2021;Pape et al, 2021;Tuan et al, 2021;Bunch et al, 2022a).…”

The Endothelial Glycocalyx: A Possible Therapeutic Target in Cardiovascular Disorders

“…Vascular aging, an important cardiovascular risk factor associated with increased vessel stifness, is characterized by microvascular dysfunction, impaired perfusion and reduced capillary density (106). In mice, glycocalyx thickness and integrity are reduced with age (107,108). A reduction of the endothelial glycocalyx thickness of ∼30% was observed also in humans with a mean age of 60 years compared to 30-year-old individuals (109).…”