TARGETING PHD/HIF SIGNALLING COMPONENTS TO MODULATE ANGIOGENESIS IN ISCHEMIC VASCULAR DISEASE

Abstract

Current therapeutic strategies for peripheral arterial disease (PAD) are focused on managing cardiovascular risks and symptoms. However, no efficient treatment exists targeting the underlying cause, limb ischemia. Enhancing endogenous angiogenesis has been proposed as a therapeutic strategy for efficient blood flow restoration. The HIF (hypoxia-inducible factor) plays a vital role in the adaptation to ischemia by enhancing angiogenesis, which can protect against ischemic damage. The protein stability of the HIF subunits is regulated by HIF-Prolyl hydroxylases (PHD). Targeting PHD enzymatic activity emerges as a therapeutic modulator of angiogenesis. However, the diverse roles of the three isoforms of HIF subunits and the three isoforms of PHD in different cellular contexts necessitate precisely tuning the optimal therapeutic targeting strategy. This study aims to assess the impact of systematically inhibiting HIF and PHD isoforms on different angiogenesis parameters using RNAi knockdown and pharmacological approaches. To frame these experimental findings clinically, we conducted a bioinformatics analysis of transcriptomic profiles across the human PAD spectrum to map isoform-specific hypoxia signaling. Our work establishes that successful vascular network formation in ischemic microenvironments is strictly dependent on the precise, dynamic balance between HIF-1 and HIF-2 activity. These insights are necessary to guide isoform-specific targeting approach to navigate this complex molecular relationship and safely restore functional angiogenesis in PAD.

Date of Award	2026
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences