PDGF-D induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis

Abstract

Platelet-derived growth factor-D (PDGF-D IntroductionPlatelet-derived growth factor (PDGF) is a mitogen for various cell types, including fibroblasts and smooth muscle cells. Although originally purified from human platelets, 1 current data indicate that several different cell types can produce PDGF in vitro and in vivo. 2 Until recently, the PDGF family of growth factors was composed of PDGF-A and PDGF-B chain homodimers and heterodimers. Recently, however, 2 novel homologous genes were isolated, PDGF-C 3 and PDGF-D. 4-6 PDGF-C and PDGF-D form disulfide-bonded homodimers, but they do not appear to heterodimerize with PDGF-A or PDGF-B chains, and they differ from the latter by having an N-terminal CUB-domain that is proteolytically cleaved before receptor binding. [3][4][5] PDGFs bind to and activate 2 structurally related protein tyrosine kinase receptors, PDGF receptor-␣ and PDGF receptor-␤. According to published data, the ␣-receptor binds PDGF-AA, PDGF-BB, PDGF-AB, and PDGF-CC, whereas the ␤-receptor binds PDGF-BB and PDGF-DD. [2][3][4] Although the exact biologic functions of PDGF-D are unknown, it has been shown to stimulate tumor growth and angiogenesis, 7-9 and it is implicated in glomerulonephritis. 10 Considerable interest focuses on the potential role of PDGF-D in wound healing. Reepithelialization, extracellular matrix deposition, and angiogenesis are all part of the wound healing process, and PDGFs are involved in various stages of this process (for a review, see Martin 11 ).Although most of the PDGF-B in wounds is produced by cells of hematopoietic origin, 12 wound healing occurs normally in mice that undergo transplantation with bone marrow derived from pdgfb null mice. 13 This result suggests a redundancy of PDGF-B-like growth factors. PDGF-D could perhaps provide a redundant function because it also binds to and activates one of the receptors for PDGF-B.Here we have addressed the effects of PDGF-D overexpression in normal skin and muscle and its effects on wound healing. We overexpressed the human PDGF-D cDNA under the keratin 14 (K14) promoter in the basal skin keratinocytes of transgenic mice. Because this promoter is strongly up-regulated during the woundhealing process, abundant PDGF-D is delivered to the wounds. 14 Furthermore, we cloned full-length PDGF-D and the activated growth factor domain into an adeno-associated virus (AAV) vector, overexpressed it alone or in combination with a known angiogenic factor, vascular endothelial growth factor-E (VEGF-E), and examined its effects on the generated blood vessels. Materials and methods Generation and analysis of K14-PDGF-D transgenic miceHuman PDGF-D cDNA (base pair [bp] 176-1285; GenBank sequence number AF336376) was inserted into the BamHI site of the K14 promoter expression vector 15 ( Figure 1A). The resultant construct was digested with EcoRI and SphI, and the expression cassette was purified. A 5-ng/mL For personal use only. on June 19, 2019. by guest www.bloodjournal.org From solution of the DNA was injected into fertilized eggs of t...

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

“…An emergent number of preclinical reports suggest that PDGF-DD is a key player in tumor formation by regulating various cellular processes, such as macrophage and stromal cell recruitment (19,26), EMT (14, 27, 28), tumor cell proliferation, and invasion (26,29,30). In human cancers, PDGFD up-regulation has been documented for prostate, lung, renal, ovarian, brain, breast, and pancreatic cancers (31,32).…”

“…Additionally, in a mouse model of wound healing, Pdgfd overexpression was accompanied by an increased recruitment of macrophages (19), a cell type associated with the angiogenic phenotype in tumors from RIP1-TAg2 mice (20). However, the immune profile of RIP1-TAg2 mice characterized by immunostaining of tumor tissue sections for a general leukocyte marker (CD45) and a macrophage marker (F4/80) did not give any evidence for gross differences in the infiltration of inflammatory cells upon Pdgfd deletion (Fig.…”

Antagonism of PDGF-D by Human Antibody CR002 Prevents Renal Scarring in Experimental Glomerulonephritis

“…Finally, CR002 led to reduced tubulointerstitial monocyte/macrophage influx, which is likely to contribute also to lesser chronic damage. In this regard, it is important to note that PDGF-D was linked recently to monocyte/macrophage infiltration in the skin (37).…”

Rationale for the development of IMC‐3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet‐derived growth factor receptor α

“…[34][35][36][37][38][39][40] PDGFRb-associated functions in cancer biology include pericyte recruitment and the regulation of interstitial fluid pressure in tumors, and the latter may affect the uptake of anticancer therapeutics into malignant tumors. [41][42][43] The Role of PDGFRa in Malignancy PDGF/PDGFRa signaling plays a relevant role in cancer biology not only because of direct effects on tumor cells but also because of paracrine effects mediated by PDGFRa expressed on tumor stroma and effects mediated through the regulation of malignant angiogenesis (Fig. 2).…”