PDGF-A Is Required for Normal Murine Cardiovascular Development

Abstract

Several lines of evidence suggest that platelet-derived growth factor A chain (PDGF-A) is required for normal embryonic cardiovascular development. To test this directly, we introduced anti-PDGF-A neutralizing antibodies into mouse deciduas in utero at Embryonic Days (E) 8.5, 9.5, and 10.5. This resulted in the selective disruption of PDGF-A ligand-receptor interactions in vivo for a period of 18-24 hr and allowed us to assess both if PDGF-A is required for cardiovascular development and when it is required. Embryos collected 48 hr after antibody treatment displayed severe cardiovascular abnormalities. These included both atrial and ventricular myocardial hypertrophy, epicardial and endocardial abnormalities, and aortic dilation, among others. Although heart abnormalities were observed in embryos treated at all three ages, they were more common in embryos treated at E8.5. In contrast, only embryos treated at E10.5 exhibited significant aortic dilation. This work (1) demonstrates directly for the first time that PDGF-A is required for normal cardiovascular development, (2) identifies several processes that require PDGF-A, and (3) defines discreet developmental periods during which these PDGF-A-dependent processes require the factor.

PDGF mediates cardiac microvascular communication.

“…Moreover, the PDGFR␣ is also regulated in angiogenesis (29), and suggested that the PDGF AB-␣ receptor communication pathway may be involved in the regulation of gene(s) critical to cardiac vascular development. Previous reports have described the importance of PDGF A and B, and PDGFR␣ in the cardiac vasculature (7)(8)(9)(10)(11)(12). PDGF ␤ receptor knockout mice have no cardiac pathology (13), but they have increases in PDGFR␣, which may result in an underestimation of the role of the ␤ receptor in the cardiac vascular PDGF communication (13).…”

Regulation and characteristics of vascular smooth muscle cell phenotypic diversity

“…24,25 In adult SMCs, these PDGF isoforms generally induce a more synthetic phenotype. For example, PDGF-B downregulates α-SMA expression in rat aortic SMCs.…”

Identification of a Cell Type-specific Enhancer in the Distal 5′-Region of the Platelet-derived Growth Factor A-chain Gene

“…Transcription of the A-chain gene is activated rapidly by a wide range of growth factors, cytokines and other mitogens (5-7), whereas complex cell type-specific patterns of A-chain transcription appear to underlie the regulation of cell proliferation during embryogenesis (8) and cellular differentiation (9). A-chain null mice exhibit abnormalities in early embryonic development and formation of lung alveolar myofibroblasts (10, 11), whereas expression of the A-chain and the PDGF ␣-receptor also appear to critical for development of the cardiovascular and nervous systems in mice (12)(13)(14). PDGF also appears to be critical for placental development, with high expression of A-chain observed in multiple cell types of the placenta including trophoblasts (2, 15), as well as extraembryonic membranes and uterine smooth muscle cells during pregnancy (15, 16).…”