Examining the evidence for vascular pathogenesis of selected birth defects

Abstract

Vascular mechanisms have been proposed to be involved in the pathogenesis of a number of defects, including transverse-limb defects, intestinal atresias, gastroschisis, hydranencephaly, porencephaly, oromandibular-limb hypogenesis sequence, and oculoauriculovertebral spectrum (OAVS). Here, we examine the available clinical, epidemiologic, and experimental evidence for four defects (transverse-limb defects, intestinal atresias, gastroschisis, and OAVS) for which vascular pathogenesis has been hypothesized. Based on our review, transverse-limb defects appear to sometimes be due to vascular events related to placental vascular abnormalities, hypoperfusion, abnormal development of blood vessels, intrauterine compression, hemoglobinopathies, or exposure to vasoactive agents, although epidemiological studies have not consistently demonstrated the latter association. However, transverse-limb defects can also be due to abnormal developmental events, such as aberrant molecular signaling in the apical ectodermal ridge. Some intestinal atresias may have a vascular origin, with the hypothesis supported by experiments in canines. However, evidence is accumulating that a more common mechanism might be related to improper molecular signaling related to gut specification early in development. In contrast, evidence to support vascular pathogenesis for gastroschisis and OAVS is less compelling. Instead, these defects probably arise from interference with basic developmental events [e.g., body wall closure (gastroschisis) and neural crest cell development (OAVS)]. These conclusions are important for counseling parents of children with these defects and for guiding the design of future epidemiological studies and experiments to further characterize the causes of these defects.

Vascular patterning regulates interdigital cell death by a ROS-mediated mechanism

“…Syndactyly associated with a decrease in embryonic oxygen supply is observed in congenital anemias, i.e. homozygous α-thalassemia, congenital dyserythropoietic anemia type I and Fanconi anemia (Abuelo et al, 1997;Adam et al, 2005;Brichard et al, 1994;Sadler and Rasmussen, 2010).…”

Comprehensive Developmental Mechanisms in Gastroschisis

“…On the other hand, this event occurs before the end of organogenesis (before 12 WD) because the mesenteric placement (the so-called rotation) is never completely achieved in gastroschisis. Intestinal atresia or perforations, if associated, are to be considered as a consequence of the mesenteric ischemia and a part of gastroschisis disease [13,23,27] . Further bowel injury, in our view, arises mainly from vascular mesenteric impairment, considering that we have never found any peel on the viscera, the blood supply of which remains within the abdomen.…”

Considering the Embryopathogenesis of VACTERL Association

“…observations]. However, the major and unresolved criticism of the vascular hypothesis is whether the vascular changes observed cause malformations or are effects of malformations [Sadler and Rasmussen, 2010]. There may be some reason to suggest that primary thrombosis/hemorrhage is an unlikely explanation for VACTERL.…”