Cardiovascular role of PDGF-B in development and disease. Studies in genetically engineered mice
Abstract
Platelet-derived growth factor B (PDGF-B) is vital for microvascular development, and retention of PDGF-B to extracellular matrix (ECM) is important in this process. However, the role and source of PDGF-B in development of macrovascular function is disputed. PDGF-B is also linked to development of vascular proliferative lesions, possibly through interaction with angiotensin II (Ang II) and endothelin-1. We studied the role of PDGF-B in development and disease, using genetically engineered mice and pharmacological inhibitors. For studies on PDGF-B retention, we used the RetKO, a mouse with targeted mutation of the retention motif - a part of the PDGF-B molecule binding to ECM. RetKO displayed primary eutrophic outward remodeling of the aorta, together with microvascular dysfunction, revealed by physical exercise tests. Eccentric cardiac hypertrophy was observed, probably secondary to the microvascular dysfunction. Similar studies were performed in endothelial-specific PDGF B knockout mice (EKO). In EKO, cardiac and macrovascular function was normal, however, physical performance was impaired, probably secondary to microvascular changes. We believe that the normal macrovascular and cardiac function in EKO are due to chimaeric competition resulting from a low recombination frequency, as observed in earlier morphological studies. To study the role of PDGF-B in development of vascular proliferative lesions, we used two mouse models carotid artery ligation as a model for low shear-induced neointimal hyperplasia, and Ang II-induced atherosclerosis in apolipoprotein E knockout mice. In both these models, PDGF-B was upregulated, however, PDGF-receptor beta (PDGFR beta) inhibition (imatinib mesylate, 100 mg/kg/day) had no effect on either plaque formation or neointimal hyperplasia. In Ang II-induced atherosclerosis, endothelin-1 was upregulated, however, unspecific endothelin receptor A/B inhibition (bosentan, 100 mg/kg/day) had no effect on atherosclerosis. Neointimal hyperplasia was accelerated by Ang II, independently of PDGFR-beta. In conclusion, retention of PDGF-B is crucial for development of adequate vascular structure and function. In microvascular development, the source of PDGF-B seems to be the endothelium, however, in macrovessels the source is unclear. No evidence was found for an important pathophysiological role of PDGF-B in Ang II-induced atherosclerosis or low shear-induced neointimal hyperplasia. However, Ang II exerted an accelerating effect on lesion progression in both these models.
University
Göteborgs universitet/University of Gothenburg
Institution
Department of Physiology
Avdelningen för fysiologi
Disputation
Hörsal Arvid Carlsson, Academicum, Medicinaregatan 3, Göteborg, kl. 09.00
Date of defence
2004-12-02
Date
2004Author
Nyström, Henrik C. 1977-
Keywords
atherosclerosis
cardiovascular disease
cell retention
in vivo physiology
neointimal hyperplasia
PDGF
transgenic mice
vascular function
vascular smooth muscle cell
Publication type
Doctoral thesis
ISBN
91-628-6306-1