Endoglin Regulates Biology and Signal Transduction in Vascular Smooth Muscle Cells
Hongyu Tian, PhD, is a Post Doctoral Research Associate at Duke University working under the direction of Dr. Gerard Blobe, Professor of Medicine and Professor of Pharmacology and Cancer Biology. In 2015, Dr. Tian was awarded a $30,000 Young Investigator Grant by Cure HHT.
Proposed Research Summary
Dr. Tian’s research examines endoglin’s roles in regulating signaling and biology in vascular smooth muscled cells (VSMCs) during developmental angiogenesis, as well as in the pathophysiology of HHT. He hypothesized that endoglin promotes VSMC recruitment by promoting VSMC migration and inhibiting VSMC proliferation through the activation of the MAPK pathway and inhibition of the PI3K/AKT pathway, respectively. With this recruitment protecting and stabilizing blood vessels during physiological vascular development, with decreased or mutated endoglin in VSMCs leading to leaky, immature blood vessels in patients with HHT.
Dr. Tian’s research study will:
- Aim 1 – Determine whether endoglin promotes VSMC recruitment by promoting VSMCs migration and/or inhibiting proliferation during developmental angiogenesis.
- Aim 2 – Determine whether endoglin promotes VSMCs recruitment and inhibits VSMC proliferation via promoting MAPK signaling and via suppressing PI3K/AKT signaling, respectively.
- Aim 3 – Determine whether mutation of endoglin in HHT decreases expression or function of endoglin in VSMCs, which results in leaky and immature blood vessels
Collectively, these studies will provide novel insights into how endoglin in vascular muscle cells regulates physiological development and how its disruption in vascular smooth muscle cells contributes to HHT. These mechanistic insights will enable novel therapies targeting endoglin function to treat HHT patients.
Research Study Update
Aim 1 – Dr. Tian’s data supports a specific role for endoglin in VSMCs in promoting VSMC recruitment and spreading on endothelial cells during angiogenesis; a cell-type dependent effect of endoglin in regulating cell migration, with endoglin in VSMC promoting VSMC migration, and endoglin in endothelial cells inhibiting endothelial migration.; that endoglin in VSMCs promotes blood vessel maturation by promoting VSMC spreading on endothelial cells via different ECM components.
Aim 2 – Dr. Tian’s data indicates that endoglin promotes FAK pathway signaling in VSMCs; that endoglin promotes VSMC recruitment and spreading at least partially via the FAK pathway; and that endoglin promotes VSMC recruitment and spreading at least in part through regulation of the integrin-FAK pathway.
Aim 3 – Dr. Tian’s data indicates that endoglin in VSMCs promotes VSMC recruitment and blood vessel maturation in vivo.
Publication – Endoglin Mediates Vascular Maturation by Promoting Vascular Smooth Muscle Cell Migration and Spreading. Arteriosclerosis, Thrombosis, and Vascular Biology 37, 1115-1126
Additional Work in Relation to HHT Research Grant
Since Angiogenesis in HHT is affected by a mutation of endoglin and the mechanism by which endoglin regulates angiogenesis is largely unknown, Dr. Tian investigated how endoglin regulates the initiation of angiogenesis by testing endoglin’s roles in vivo using a tumor model.
Publication – Endoglin Interacts with VEGFR2 to Promote Angiogenesis. The FASEB Journal Vol. 32 June 2018
Lay Summary of Additional Work