Endothelial Apoptosis as the Primary Lesion Initiating Intestinal Radiation Damage in Mice

Abstract

Gastrointestinal (GI) tract damage by chemotherapy or radiation limits their efficacy in cancer treatment. Radiation has been postulated to target epithelial stem cells within the crypts of Lieberkühn to initiate the lethal GI syndrome. Here, we show in mouse models that microvascular endothelial apoptosis is the primary lesion leading to stem cell dysfunction. Radiation-induced crypt damage, organ failure, and death from the GI syndrome were prevented when endothelial apoptosis was inhibited pharmacologically by intravenous basic fibroblast growth factor (bFGF) or genetically by deletion of the acid sphingomyelinase gene. Endothelial, but not crypt, cells express FGF receptor transcripts, suggesting that the endothelial lesion occurs before crypt stem cell damage in the evolution of the GI syndrome. This study provides a basis for new approaches to prevent radiation damage to the bowel.

Irradiation to the Young Mouse Brain Caused Long-Term, Progressive Depletion of Neurogenesis but did not Disrupt the Neurovascular Niche

“…In addition, others have emphasized the importance of microvessels in radiotherapy since preventing endothelial apoptosis pharmacologically could rescue stem cell dysfunction of the intestinal crypt. 35 Furthermore, the vascular-specific radioprotective agent WR-2721 (amifostine, Ethyol), which does not pass the blood-brain barrier, could decrease the number of animals developing radionecrosis following 25 Gy irradiation to the brain. 36 On the other hand, the importance and involvement of microvessels in stem cell ablation after irradiation has been questioned in a study by Otsuka et al 37 They compared the effect on immature neural precursor cells when targeting the vessels specifically or the parenchyma uniformly and found that the neural precursor cells where less affected when the irradiation targeted only the microvasculature compared with the entire parenchyma, indicating that other factors than microvessels contribute to the irradiation-induced damage.…”

In Vivo Blockade of Tumor Necrosis Factor-α Accelerates Functional Endothelial Recovery After Balloon Angioplasty

“…16 The present findings suggest that TNF may also negatively regulate the recovery of the endothelium after angioplasty. Data from clinical trials of intracoronary brachytherapy for the prevention of stent restenosis, suggesting that the inhibition of re-endothelialization, possibly mediated by radiation induced endothelial cell apoptosis, 17 was associated with a marked increase in stent thrombosis 18 has highlighted the importance of endothelial recovery in optimizing clinical outcome after percutaneous coronary intervention. The present data suggest that inhibiting TNF effects after angioplasty may represent a strategy that could be used independently for restenosis prevention or to complement other therapies, such as those targeting smooth muscle cell proliferation.…”

Regulation of adult intestinal epithelial stem cell development by thyroid hormone during Xenopus laevis metamorphosis

“…It is generally known that the microenvironment around the stem cells known as the "niche" plays key roles in this epithelial cell-renewal (Potten et al, 1997;Mills and Gordon, 2001). Recently, several types of cells including subepithelial myofibroblasts (Powell et al, 1999), endothelial cells (Paris et al, 2001), intraepithelial lymphocytes (Komano et al, 1995), and enteric neurons (Bjerknes and Cheng, 2001) have been proposed as "niche players," which affect the stem cells and their descendants. However, only fragmentary information is available on their functions at the molecular level.…”