Analysis of PDGF-BB Signaling and Soluble PDGFRb in Pericyte-Endothelial Interactions: Insights From Placental and Cerebrovascular Systems

Abstract

During early embryonic and placental development, vascular networks undergo extensive morphological changes and remodeling, requiring tightly coordinated interactions between endothelial cells (ECs) and pericytes (PCs). PC recruitment to ECs, primarily regulated by the platelet-derived growth factor-BB (PDGF-BB)/PDGFRβ signaling pathway, is essential for microvascular stability and maturation. While soluble PDGFRβ (sPDGFRβ) has been widely associated with pericyte injury and vascular dysfunction in aging and disease, its role in early development remains unclear. This dissertation investigated the regulation, origin, and functional significance of sPDGFRβ isoforms across developmental and physiological contexts, with a particular focus on vascular and placental systems. A comprehensive literature review highlights the importance of PC-EC crosstalk and key molecular regulators, including PECAM-1, Notch, collagen type IV, vitonectin, and NG2. As well as major growth factor pathways such as VEGF, PDGF, and PlGF in coordinating vascular development. Experimental analyses demonstrate the NG2-positive PCs are present on both human and murine placentas, with evidence of early recruitment during development. Soluble PDGFRβ (sPDGFRβ) i4 isoform increases throughout gestation, correlating with placental growth and maturation, while the i10 isoform is responsive to environmental stressors such as hypoxia. Findings from mouse embryonic stem cell models suggest that sPDGFRβ generation during development is likely driven my pre-mRNA splicing. Functional studies further indicate that sPDGFRβ potentially acts as a modulator of PDGF signaling, with possible influence on pericyte behavior and vascular stability. Additionally, investigations in the brain reveal that sPDGFRβ isoforms are present under normal physiological conditions and are upregulated in response to hypoxia and aging. There are two isoforms, i4 and i10, of sPDGFRβ and they may function similarly to other soluble receptors, such as sFlt-1, to maintain signaling balance. This work also includes an optimized method for isolating brain capillaries using density gradient centrifugation and filtration. This method enables improved study of blood brain barrier (BBB) microvasculature, though limitations remain in fully excluding larger vessels. Collectively, this work establishes sPDGFRβ as a dynamically regulated component of PDGF signaling in both development and physiological contexts, rather than solely a marker of pathology. These findings highlight a critical gap in understanding the role of sPDGFRβ during early development and suggest its potential as a biomarker and therapeutic target in vascular related disorders, including placental dysfunction and neurovascular disease.