Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation

Abstract

Thalidomide is a potent teratogen that induces a range of birth defects, most commonly of the developing limbs. The mechanisms underpinning the teratogenic effects of thalidomide are unclear. Here we demonstrate that loss of immature blood vessels is the primary cause of thalidomide-induced teratogenesis and provide an explanation for its action at the cell biological level. Antiangiogenic but not antiinflammatory metabolites/analogues of thalidomide induce chick limb defects. Both in vitro and in vivo, outgrowth and remodeling of more mature blood vessels is blocked temporarily, whereas newly formed, rapidly developing, angiogenic vessels are lost. Such vessel loss occurs upstream of changes in limb morphogenesis and gene expression and, depending on the timing of drug application, results in either embryonic death or developmental defects. These results explain both the timing and relative tissue specificity of thalidomide embryopathy and have significant implications for its use as a therapeutic agent.blood vessels ͉ chick limb development ͉ thalidomide analog ͉ angiogensis ͉ zebrafish

Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures

“…An alternative explanation to the observed shortened femoral length is that hematopoiesis in the femur could lead to more severe hypoxia of its growth plate than in other bones, although this explanation seems unlikely because the bone marrow in A10⌬EC mice contains substantially less hematopoietic cells than the bone marrow in controls. These results support the notion that abnormal vascularization in developing long bones can make a significant contribution to the pathogenesis of phocomelia in humans, 45 although additional studies will be required to understand the cause of the shortened femurs in A10⌬EC mice. The splenic extramedullary hematopoiesis and peripheral reticulocytosis in A10⌬EC mice is presumably secondary to peripheral hemolysis, a notion that is supported by the observation that hematocrit, hemoglobin and red blood cell count are lower than in controls.…”

Thalidomide‐induced teratogenesis: History and mechanisms

“…Blood vessels were rapidly destroyed within 1 hr of exposure in the embryo and several hours before any changes in limb signaling gene expression and cell death was observed (Therapontos et al, 2009; Vargesson, 2009, 2013). Reduction in limb area was seen after 6 hr.…”

“…Several nonantiangiogenic analogs and hydrolysis products of thalidomide tested using the same assays were found to not be teratogenic or obviously harmful to chicken embryos (Therapontos et al, 2009). This indicates that the antiangiogenic action of the drug can cause a wide range of limb defects in a time‐dependent manner.…”

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

“…As for Bevazicimub, a chance observation in an HHT patient undergoing treatment for cancer 190 led to case reports 191 and a small series 31 indicating a Blood Reviews _ HHT 2010_ Shovlin 18 potential role in HHT. Recent mechanistic data indicate that thalidomide exhibits differential effects on immature blood vessel networks 192,193 , and dose-dependent effects on angiogenesis are proposed 31 . Thalidomide appears to target mural cell recruitment, by increasing endothelial expression of PDGF-B at the endothelial tip cell thus facilitating recruitment of pericytes that express PDGFR-b, associated with increasing pericyte proliferation 31 .…”