Phosphatidylserine Translocation after Radiosurgery in an Animal Model of Arteriovenous Malformation

Abstract

Phosphatidylserine (PS) is asymmetrically distributed across the plasma membrane, located predominantly on the inner leaflet in healthy cells. Translocation of PS to the outer leaflet makes it available as a target for biological therapies. We examined PS translocation after radiosurgery in an animal model of brain arteriovenous malformation (AVM). An arteriovenous fistula was created by end-to-side anastomosis of the left external jugular vein to the common carotid artery in 6-week-old, male Sprague Dawley rats. Six weeks after AVM creation, 15 rats underwent Gamma Knife stereotactic radiosurgery receiving a single 15 Gy dose to the margin of the fistula; 15 rats received sham treatment. Externalization of PS was examined by intravenous injection of a PS-specific near-infrared probe, PSVue-794, and in vivo fluorescence optical imaging at 1, 7, 21, 42, 63 and 84 days postirradiation. Fluorescent signaling indicative of PS translocation to the luminal cell surface accumulated in the AVM region, in both irradiated and nonirradiated animals, at all time points. Fluorescence was localized specifically to the AVM region and was not present in any other anatomical sites. Translocated PS increased over time in irradiated rats (P < 0.001) but not in sham-irradiated rats and this difference reached statistical significance at day 84 (P < 0.05). In summary, vessels within the mature rat AVM demonstrate elevated PS externalization compared to normal vessels. A single dose of ionizing radiation can increase PS externalization in a time-dependent manner. Strict localization of PS externalization within the AVM region suggests that stereotactic radiosurgery can serve as an effective priming agent and PS may be a suitable candidate for vascular-targeting approaches to AVM treatment.

The Evolution of Safe and Effective Coaguligands for Vascular Targeting and Precision Thrombosis of Solid Tumors and Vascular Malformations

“…While PS targeting in tumors has been more avidly pursued in the context of cancer immunotherapy [35], it has been investigated as a radiation-stimulated target for vascular infarction in brain AVMs [36][37][38][39][40]. Thorpe and colleagues demonstrated that translocation of this phospholipid to the surface of tumor vessels could be enhanced in response to oxidative stress, via stimulation by growth factors, hydrogen peroxide, and ionizing radiation [28,41,42].…”

Externalization of Mitochondrial PDCE2 on Irradiated Endothelium as a Target for Radiation-Guided Drug Delivery and Precision Thrombosis of Pathological Vasculature

“…To date, various endogenous markers have been identified on tumor vasculature and investigated in mouse tumor infarction models (reviewed in [ 1 ]). However, limitations to endogenous biomarker discovery in brain arteriovenous malformations (AVMs) have led to the use of ionizing radiation as a priming agent for target generation in this context [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ].…”

“…Radiation damage sets off a cascade of cellular events in endothelial cells that can alter the molecules or proteins at the cell surface (surfaceome) [ 4 , 5 , 15 , 16 ]. Surface exposure of common inflammatory markers such as phosphatidylserine (PS), vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) have been previously investigated as radiation-stimulated targets in an AVM animal model [ 6 , 7 , 13 , 17 ]. However, their frequent exposure in response to other biological stimuli may reduce targeting specificity.…”

Radiation-Stimulated Translocation of CD166 and CRYAB to the Endothelial Surface Provides Potential Vascular Targets on Irradiated Brain Arteriovenous Malformations

“…Vascular targeting was first described in cancer therapy to deliver thrombotic agents for tumor vessel destruction that capitalizes on the inherent molecular differences between tumor endothelium and normal, healthy endothelium that can be used to target agents selectively to the site of disease [3,4]. To date, no inherent, discriminatory vascular markers have been identified on human AVMs, hence we proposed that a combination of focused radiosurgical priming and vascular targeting may be an effective approach for AVM cure [5,6,7,8,9,10,11]. Radiation has previously been used to enhance target expression on tumor vasculature [12,13].…”