Vascular Pattern and Limb Development : 1. Normal development of the hindlimb vasculature in the mouse and its aberrations induced by 5-fluorouracil

The role of the vascular system in normal and abnormal limb morphogenesis is still a controversial subject. The present study was designed to examine the normal development of the mouse hindlimb vasculature, including the arterial pattern of the adult mouse, and the relationship between the time of teratogen administration and the resulting alteration in vascular and skeletal patterns. Polydactylies were induced in developing mouse hindlimbs by a single intraperitoneal injection of 5-fluorouracil (5-FU) in a dose of 30 mg/kg of maternal body weight at day 10.5 of pregnancy (vaginal plug= day 0; Theiler's stage T. S. 18), and reductive malformations were induced in developing mouse hindlimb in same way at day 11.5 of pregnancy (T. S. 20). For observation of gross vascular patterns, India ink was injected into the vitelline vein of embryos and fetuses at various stages between day 11.0 (T. S. 19) and day 15.5 (T. S. late 24) of pregnancy.

In normal development, the main vessels of the leg are formed by day 13.5 (T. S. early 23) of pregnancy and the vessels of the toes become evident by day 15.5. In the polydactylous limbs resulting from treatment with 5-FU at day 10.5, vascular changes were observed mainly in the foot and not in the leg. In the limbs with reductive malformations induced by treatment at day 11.5, aberrant vascular patterns were noted in the leg as well as in the foot.

In man, many cases of arterial anomalies in the malformed upper limbs have been described and interpreted as indicator of the time of teratogenic event by a few investigators. They assumed that the aberrant vessel had been just forming at the time of teratogenic event. However, the results of the present experiment clearly demonstrated that there were some gaps between the time estimated from the altered arterial pattern and the real time of teratogen administration. It is concluded that abnormal arterial pattern in a malformed limb does not directly indicate the time of teratogenic event, but reflects an abnormal patterning of mesenchymal condensations.