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Calcitonin Gene-Related Peptide (CALCA) Is a Proangiogenic Growth Factor in the Human Placental Development¹

Departments of Obstetrics and Gynecology³ and Human Biological Chemistry and Genetics,⁴ University of Texas Medical Branch, Galveston, Texas 77555-1062

ABSTRACT

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.

angiogenesis,, CALCA, decidua, placenta, trophoblast

¹Supported by National Institutes of Health grants HL70883, HD50266, and HL58144.

Correspondence: ²Yuan-Lin Dong, Department of Obstetrics and Gynecology, University of Texas Medical Branch, 301 University Blvd., MRB, 11.138, Rt. 1062, Galveston, TX 77555-1062. FAX: 409 747 0475; e-mail: ydong{at}utmb.edu