Angiostatic cues from the matrix: Endothelial cell autophagy meets hyaluronan biology

Abstract

The extracellular matrix encompasses a reservoir of bioactive macromolecules that modulates a cornucopia of biological functions. A prominent body of work posits matrix constituents as master regulators of autophagy and angiogenesis and provides molecular insight into how these two processes are coordinated. Here, we review current understanding of the molecular mechanisms underlying hyaluronan and HAS2 regulation and the role of soluble proteoglycan in affecting autophagy and angiogenesis. Specifically, we assess the role of proteoglycan-evoked autophagy in regulating angiogenesis via the HAS2-hyaluronan axis and ATG9A, a novel HAS2 binding partner. We discuss extracellular hyaluronan biology and the post-transcriptional and post-translational modifications that regulate its main synthesizer, HAS2. We highlight the emerging group of proteoglycans that utilize outside-in signaling to modulate autophagy and angiogenesis in cancer microenvironments and thoroughly review the most up-to-date understanding of endorepellin signaling in vascular endothelia, providing insight into the temporal complexities involved.

Keywords: AMP-activated kinase (AMPK); angiogenesis; autophagy; cell signaling; decorin; endothelial cell; extracellular matrix; hyaluronan; hyaluronan synthase 2; perlecan; proteoglycan; vascular biology.

Figure 1

ECM signaling in autophagy and angiogenesis.A, an overview of cell-surface proteoglycan signaling of endorepellin, decorin, endostatin, biglycan, and lumican resulting in modulations on autophagy and/or angiogenesis. Cell types range from endothelial cells to macrophages to pancreatic ductal adenocarcinoma (PDAC). B, summary of pro-angiogenic HA signaling starting with synthesis of HA from GlcUA and GlcNAc by HASs at the plasma membrane and ending with the subsequent degradation of HMW HA into LMW polysaccharides.

Figure 2

Comprehensive schematic of transient endorepellin signaling in vascular endothelia. The transient signaling cascade downstream of endorepellin binding begins within 30 min of endorepellin treatment in which endorepellin behaves as a dual receptor antagonist of VEGFR2 and α2β1 integrin.

Figure 3

Comprehensive schematic of sustained endorepellin signaling in vascular endothelia. The long-term, sustained signaling cascade downstream of endorepellin binding occurs around 2–6 h in which endorepellin behaves as a partial agonist of VEGFR2 where it modulates mitochondrial homeostasis, autophagic flux, stress signaling, and angiogenesis.

Figure 4

Schematic of endorepellin-evoked catabolism of HAS2 in vascular endothelia resulting in angiostasis. Autophagic degradation of HAS2 and suppression of HA secretion is the critical link in sustained endorepellin signaling between activation of autophagic flux and angiostasis.