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Abstract 17312: Hand1 Impairs Angiogenesis in Heart and Placenta


 Introduction:
 Congenital heart defects affect approximately 1% of live births, often requiring complex surgeries at birth. The most significant risk factor for surgery survival is birthweight. Proper placental development and function is vital for normal fetal growth. We have previously demonstrated abnormal placental development and vascularization in human CHD placentas. Hand1 has roles in heart and placental development and has been implicated in multiple types of CHD including double right outlet, hypoplastic left heart syndrome, and septal defects. We utilized the Hand1
 A126fs/+
 mouse to investigate the role of Hand1 in placentation and vascularization.
 
 
 Methods:
 Hand1
 A126fs/+
 female mice were time-mated with Nkx2.5cre or Cdh5cre males. Feto-placental units were harvested at E10.5 and E12.5 for histological analysis, vascular assessment by IHC for CD-31, and RNA expression by qPCR.
 
 
 Results:
 Nkx2.5cre/Hand1
 a126fs/+
 fetuses demonstrated embryonic lethality by E10.5 due to lack of placental labyrinth formation and vascularization (Figure 1). In contrast, ablation of Hand1 in vascular endothelium (Cdh5cre) did not disrupt placental labyrinth or heart at E12.5. Expression of VegFb, Ang1, Ang2, Flt1, Flk was reduced in Hand1
 A126fs/+
 ; Nkx2.5cre placentas compared to control littermates, but VegFa expression was increased.
 
 
 Conclusion:
 Our data demonstrate that Hand1 expression in placental trophoblast, but not endothelium, is necessary for vascularization of the labyrinth and may disrupt multiple angiogenic factors known to be expressed in trophoblast. Alterations in Hand1 may represent a mechanism for abnormal placentation in cases of CHD.
 
 
 
 
 
 Figure 1. H/E (A-C) and CD31 (D-F) images of Hand1
 +/+
 (A, D), Hand1
 A126fs/+
 ; Nkx2.5cre (B, E), and Hand1
 A126fs/+
 ; Cdh5cre (C, F) placentas at day E12.5. Hand1A
 126fs/+
 ; Nkx2.5cre placentas fail to form labyrinth and fetal vasculature, while Hand1
 A126fs/+
 ; Cdh5cre placentas develop normally at this timepoint.
