Collateral Vessels Have Unique Endothelial and Smooth Muscle Cell Phenotypes

Abstract

Collaterals are unique blood vessels present in the microcirculation of most tissues that, by cross-connecting a small fraction of the outer branches of adjacent arterial trees, provide alternate routes of perfusion. However, collaterals are especially susceptible to rarefaction caused by aging, other vascular risk factors, and mouse models of Alzheimer’s disease—a vulnerability attributed to the disturbed hemodynamic environment in the watershed regions where they reside. We examined the hypothesis that endothelial and smooth muscle cells (ECs and SMCs, respectively) of collaterals have specializations, distinct from those of similarly-sized nearby distal-most arterioles (DMAs) that maintain collateral integrity despite their continuous exposure to low and oscillatory/disturbed shear stress, high wall stress, and low blood oxygen. Examination of mouse brain revealed the following: Unlike the pro-inflammatory cobble-stoned morphology of ECs exposed to low/oscillatory shear stress elsewhere in the vasculature, collateral ECs are aligned with the vessel axis. Primary cilia, which sense shear stress, are present, unexpectedly, on ECs of collaterals and DMAs but are less abundant on collaterals. Unlike DMAs, collaterals are continuously invested with SMCs, have increased expression of Pycard, Ki67, Pdgfb, Angpt2, Dll4, Ephrinb2, and eNOS, and maintain expression of Klf2/4. Collaterals lack tortuosity when first formed during development, but tortuosity becomes evident within days after birth, progresses through middle age, and then declines—results consistent with the concept that collateral wall cells have a higher turnover rate than DMAs that favors proliferative senescence and collateral rarefaction. In conclusion, endothelial and SMCs of collaterals have morphologic and functional differences from those of nearby similarly sized arterioles. Future studies are required to determine if they represent specializations that counterbalance the disturbed hemodynamic, pro-inflammatory, and pro-proliferative environment in which collaterals reside and thus mitigate their risk factor-induced rarefaction.

The progeria research foundation 10th international scientific workshop; researching possibilities, ExTENding lives – webinar version scientific summary

“…In both of these measures, children with Progeria display clinically consequential abnormalities that can be partly alleviated by Zokinvy therapy. In both aging adults and in Progeria, collateral vessels develop in response to a relative lack of blood supply to the brain through the major vasculature [ 36 ]. These vessels provide essential blood supply but are generally fragile and more susceptible to bleeding.…”

Structural and Functional Remodeling of the Brain Vasculature Following Stroke

“…Indeed, proper collateral vascular responses in stroke can significantly affect stroke outcome and mortality (Kimmel et al, 2019;Nannoni et al, 2019). However, current understanding of collateral vessel dynamics is not clear; interestingly, a recent study reported that collateral vessels have distinct endothelial and smooth muscle cell phenotypes (Zhang et al, 2019). Understanding the molecular factors that govern collateral responses to brain injury may illuminate new avenues for therapeutic approaches.…”

Role of sphingosine‐1‐phosphate receptors in vascular injury of inflammatory bowel disease

“…Chronic inflammation is often associated with increased angiogenesis, which is a key contributor to the maintenance of chronic inflammation in gastrointestinal tract 39 . Blood vessels are mainly composed of endothelial cells and parietal cells (vascular smooth muscle cells and pericytes) 40 . Angiogenesis normally originates from the sprouting of endothelial cells, followed by the destruction of blood vessel walls and the proliferation and migration of endothelial cells 41 .…”

“…39 Blood vessels are mainly composed of endothelial cells and parietal cells (vascular smooth muscle cells and pericytes). 40 Angiogenesis normally originates from the sprouting of endothelial cells, followed by the destruction of blood vessel walls and the proliferation and migration of endothelial cells. 41 The angiogenic process is tightly regulated by a wide array of angiogenic factors.…”