Pulmonary hypertension : the role and place of PDGF

Abstract

Pulmonary hypertension is a severe condition, leading to right heart dysfunction and preterm death. For pulmonary arterial hypertension (PAH), a disease group in which the primary pathology resides within the pulmonary pre-capillary vessels, several specific therapies are in clinical use, but unfortunately the prognosis is still grim. Available PAH therapy mainly targets vasoconstriction and the progressive vascular remodeling is not adequately suppressed. Considering biological similarities to malignancies, hypotheses and therapies from cancer research have been tested in PAH. An example of this is imatinib, originally designed to target a mutated receptor in chronic myeloid leukemia, and found to also inhibit platelet-derived growth factor (PDGF) signaling. Albeit to some extent efficient, imatinib is unspecific and leads to severe side effects in PAH patients.

Previous studies have found PDGF receptor b and its ligand, PDGF-B, to be implicated in PAH. PDGF signaling is known to induce cell proliferation, migration, and extracellular matrix deposition. Additionally, PDGF-B contains a retention motif that binds to matrix proteoglycans, such as perlecan. Perlecan, which has previously been shown to affect vascular remodeling in the systemic circulation, has here been investigated in the pulmonary circulation. Further, the role of PDGF-D, the other known ligand of PDGF receptor b, has in this thesis been characterized in physiology as well as in pulmonary hypertension.

Paper I and II combined describes how pulmonary vascular remodeling could be altered by either targeting the PDGF-B retention motif or perlecan heparan sulfate (HS). In development, perivascular smooth muscle cells and pericytes propagate towards an extracellular PDGF-B gradient. Our findings support previous reports on similar mechanisms also in hypoxia-induced pulmonary vascular remodeling. Further, we show that perlecan HS promotes fibroblast growth factor signaling, another important mitogen for smooth muscle cells and pericytes.

In paper III, effects of PDGF-D deletion were thoroughly characterized. Pdgfd-/- mice were shown to be viable and healthy, however a mild cardiovascular phenotype, including discrete alterations in pericyte attachment to cardiac microvessels, was found. In Paper IV the role of PDGF-D in PH was explored. It was shown to be present in vascular lesions of PAH patients and recombinant PDGF-D potently induced proliferation of human and mouse pulmonary arterial smooth muscle cells in vitro. This suggested that PDGF-D could be a driver of pulmonary vascular remodeling. However, Pdgfd-/- mice were not protected against disease and hence, PDGF-D seems to be a redundant mitogen in hypoxia-induced PH.

The collected work of this thesis highlights the importance of spatial distribution of growth factors and prompts future PAH studies to take the extracellular matrix into consideration.