A Tissue-Specific Soluble Platelet-Derived Growth Factor Receptor-beta Isoform Retains Functional Capacity - PROJECT SUMMARY / ABSTRACT Microvascular dysfunction underlies a wide range of devastating diseases, from Alzheimer’s Disease to cancer. However, mechanisms underlying vessel maintenance that become dysregulated in vascular-related pathologies are still emerging, fueling the advancement of blood-based diagnostics and bioengineered therapeutics. We recently identified a truncated, alternative splice variant of Platelet-Derived Growth Factor Receptor-β (PDGFRβ) that encodes a soluble PDGFRβ isoform (sPDGFRβ), which may harbor potential as a future diagnostic and therapeutic target. Receptor tyrosine kinases (RTKs), like PDGFRβ, often have soluble counterparts that are generated via alternative splicing to function as “decoy” receptors to negatively regulate ligand-induced signaling of the full-length receptor. Full-length PDGFRβ is expressed by pericytes (PCs) to mediate their recruitment to microvascular endothelial cells (ECs) producing the cognate ligand Platelet-Derived Growth Factor BB (PDGF- BB) – where PCs promote vessel stability and tune permeability. However, microvascular PC density and vessel permeability vary between tissues and specialized vascular beds, with vessel dysfunction often associated with PC loss and misregulated PDGFRβ--PDGF-BB signaling. Thus PDGFRβ-mediated PC recruitment is vital to vessel integrity, although the exact mechanisms that govern it remain unclear. Recent studies report a large sPDGFRβ produced via proteolytic cleavage in cerebral pathology scenarios. However, our data indicate that a small sPDGFRβ is generated via alternative splicing in a broad range of normal, healthy tissues, though it is also likely involved in disease states. We recently elucidated the full mRNA sequence of sPdgfrb, enabling targeted manipulation and analysis approaches. In addition to broad and differential expression across various tissues, our preliminary findings indicate overlap with full-length Pdgfrb (fPdgfrb)-expressing cells in mouse brain, and presence of immunolabled, non-vessel associated sPDGFRβ protein signal in the brain parenchyma. These findings, considered alongside established mechanisms of ligand sequestration in related RTKs, inform our hypothesis that PDGF-BB bioavailability is regulated by alternatively spliced sPDGFRβ to mediate PC-vessel recruitment and tune vessel permeability. Therefore, using complementary in vitro and in vivo models, we propose investigation of sPDGFRβ potential to bind and regulate (i) PDGF-BB bioavailability, (ii) activation of full-length PDGFRβ (fPDGFRβ), (iii) PC dynamics, and (iv) developing vessel morphology and permeability. We will investigate sPDGFRβ cell-specificity, and spatio-temporal distribution in various tissues to determine the extent of its functional role. In addition, we will assess the potential of sPDGFRβ as a biomarker and treatment in vascular-related pathologies involving PC loss. This work will advance our understanding of mechanisms underlying vessel maintenance and integrity, and lay the groundwork for follow-on collaborative studies aiming to develop sPDGFRβ as a potential diagnostic tool and therapeutic target in cardiovascular diseases.
