Annica Ponten

PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor.

Platelet-derived growth factors (PDGFs) are important in many types of mesenchymal cell. Here we identify a new PDGF, PDGF-C, which binds to and activates the PDGF α-receptor. PDGF-C is activated by proteolysis and induces proliferation of fibroblasts when overexpressed in transgenic mice. In situ hybridization analysis in the murine embryonic kidney shows preferential expression of PDGF-C messenger RNA in the metanephric mesenchyme during epithelial conversion. Analysis of kidneys lacking the PDGF α-receptor shows selective loss of mesenchymal cells adjacent to sites of expression of PDGF-C mRNA; this is not found in kidneys from animals lacking PDGF-A or both PDGF-A and PDGF-B, indicating that PDGF-C may have a unique function.

Vascular Endothelial Growth Factor-B–Deficient Mice Display an Atrial Conduction Defect

Background—Vascular endothelial growth factors (VEGFs) and their receptors are essential regulators of vasculogenesis and angiogenesis in both embryos and adults. One of the factors with a still unknown physiological function is VEGF-B, which is expressed in many tissues, including the heart. Methods and Results—Mice carrying a targeted deletion in the VEGF-B gene were developed. In VEGF-B−/− animals, no gross abnormalities were observed in organs that normally show high expression of VEGF-B, such as the heart, muscle, and kidney. Analysis of heart function by ECG showed that adult VEGF-B−/− mice have an atrial conduction abnormality characterized by a prolonged PQ interval. VEGF- or basic fibroblast growth factor–induced corneal angiogenesis was similar in normal and VEGF-B−/− mice. Conclusions—VEGF-B seems to be required for normal heart function in adult animals but is not required for proper development of the cardiovascular system either during development or for angiogenesis in adults.

Revascularization of ischemic tissues by PDGF-CC via effects on endothelial cells and their progenitors

The angiogenic mechanism and therapeutic potential of PDGF-CC, a recently discovered member of the VEGF/PDGF superfamily, remain incompletely characterized. Here we report that PDGF-CC mobilized endothelial progenitor cells in ischemic conditions; induced differentiation of bone marrow cells into ECs; and stimulated migration of ECs. Furthermore, PDGF-CC induced the differentiation of bone marrow cells into smooth muscle cells and stimulated their growth during vessel sprouting. Moreover, delivery of PDGF-CC enhanced postischemic revascularization of the heart and limb. Modulating the activity of PDGF-CC may provide novel opportunities for treating ischemic diseases.

Transgenic overexpression of platelet-derived growth factor-C in the mouse heart induces cardiac fibrosis, hypertrophy, and dilated cardiomyopathy.

The platelet-derived growth factors are implicated in development of fibrotic reactions and disease in several organs. We have overexpressed platelet-derived growth factor-C in the heart using the alpha-myosin heavy chain promoter and created a transgenic mouse that exhibits cardiac fibrosis followed by hypertrophy with sex-dependent phenotypes. The transgenic mice developed several pathological changes including cardiac fibroblast proliferation and deposition of collagen, hypertrophy, vascular defects, and the presence of Anitschkow cells in the adult myocardium. Male mice developed a hypertrophic phenotype, whereas female mice were more severely affected and developed dilated cardiomyopathy, leading to heart failure and sudden death. The vascular defects initially included dilation of microvessels and vascular leakage. Subsequently, a marked loss of microvessels, formation of large vascular sac-like structures, and an increased density of smooth muscle-coated vessels were observed in the myocardium. In part, the observed vascular changes may be because of an up-regulation of vascular endothelial growth factor in cardiac fibroblasts of the transgenic hearts. This unique animal model reveals that a potent mitogen for cardiac fibroblasts result in an expansion of the interstitium that induce a secondary sex-dependent hypertrophic response in the cardiomyocytes.

Platelet-Derived Growth Factor D Induces Cardiac Fibrosis and Proliferation of Vascular Smooth Muscle Cells in Heart-Specific Transgenic Mice

Platelet-derived growth factor (PDGF)-D is a member of the PDGF/vascular endothelial growth factor family that activates PDGF receptor β (PDGFR-β). We show that PDGF-D is highly expressed in the myocardium throughout development and adulthood, as well as by arterial vascular smooth muscle cells (vSMCs). To obtain further knowledge regarding the in vivo response to PDGF-D, we generated transgenic mice overexpressing the active core domain of PDGF-D in the heart. Transgenic PDGF-D stimulates proliferation of cardiac interstitial fibroblasts and arterial vSMCs. This results in cardiac fibrosis followed by dilated cardiomyopathy and subsequent cardiac failure. Transgenic mice also display vascular remodeling, including dilation of vessels, increased density of SMC-coated vessels, and proliferation of vSMCs, leading to a thickening of tunica media. The thickening of arterial walls is a unique feature of PDGF-D, because this is not seen when PDGF-C is overexpressed in the heart. These results show that PDGF-D, via PDGFR-β signaling, is a potent modulator of both vascular and connective tissue growth and may provide both paracrine and autocrine stimulation of PDGFR-β. Our data raise the possibility that this growth factor may be involved in cardiac fibrosis and atherosclerosis.