Calcitonin gene-related peptide (CALCA) is a proangiogenic growth factor in the human placental development.
Recent studies have shown that homozygous knockout of gene for calcitonin gene-related peptide (CALCA) receptor component, calcitonin receptor-like receptor (CALCRL), led to extreme hydrops fetalis and embryonic death, underlining the critical role of CALCA in embryonic development and fetal growth. The present study was designed to determine the cellular localization of CALCA and its receptor components, CALCRL and receptor activity modifying protein 1 (RAMP1), at the human implantation site during early pregnancy; to assess whether CALCA regulates in vitro angiogenesis of human endothelial cells; and to examine whether CALCA can improve angiogenic imbalance in preeclamptic placental explants. Our studies demonstrated that both protein and mRNA for CALCA were expressed by the villous and extravillous trophoblasts and decidual cells in the first-trimester villous tissues. CALCA receptor components, CALCRL and RAMP1, were expressed by both villous and extravillous trophoblast cells, as well as vascular endothelial cells. CALCA induced both endothelial proliferation and migration in a dose- and time-dependent manner, and it promoted capillarylike tube formation of human umbilical vein endothelial cells (HUVECs) on Matrigel. CALCA-induced angiogenesis of human endothelial cells was completely blocked by CALCA antagonist CALCA(8-37). Further, conditioned medium from preeclamptic placental explants significantly inhibited HUVEC capillarylike tube formation compared with gestational age-matched controls, and conditioned medium from preeclamptic placental explants incubated with CALCA significantly improved capillarylike tube formation. We conclude that CALCA induces in vitro angiogenesis by stimulating endothelial cell proliferation, migration, and capillarylike tube formation; thus, CALCA at the human implantation site may constitute a potential autocrine or paracrine mechanism that could modify placental angiogenesis and neovascularization.
Dong
Yuan-Lin
YL
Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555-1062, USA. ydong@utmb.edu
Reddy
Deepti M
DM
Green
Kortney E
KE
Chauhan
Madhu S
MS
Wang
Hui-Qun
HQ
Nagamani
Manubai
M
Hankins
Gary D V
GD
Yallampalli
Chandra
C
D015740:Calcitonin Gene-Related Peptide / Q000502:physiology*; D002196:Capillaries / Q000254:growth & development; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002824:Chorionic Villi / Q000502:physiology; D003656:Decidua / Q000166:cytology / Q000254:growth & development; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D047109:Fetal Development / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018613:Microscopy, Confocal; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D010929:Placentation; D011225:Pre-Eclampsia / Q000473:pathology; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014327:Trophoblasts / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology
D012333:RNA, Messenger; D015740:Calcitonin Gene-Related Peptide