Hanqiang Deng, PhD

1. Identify MEKK3-CCM2 complex and its function to maintain vascular integrity and permeability: During my PhD training, I worked on the role of endothelial MEKK3 in embryonic and neonatal stages. We found that deletion of MEKK3 in mice at both stages lead to lethality because of impaired vascular integrity. We discovered direct interaction between N-terminal of MEKK3 and CCM2 harmonin homology domain (HHD) and determined a cocrystal structure. Moreover, MEKK3 endothelial deficiency impairs vascular integrity is partially dependent on Rho-ROCK signaling and disruption of MEKK3-CCM2 interaction leads to similar vascular leakage with MEKK3 endothelial knockout [1].
2. Discover endothelial MEKK3 as an unexpected regulator of artery inward remodeling leading to pulmonary and systemic hypertension: After graduation, I moved to Yale School of Medicine for postdoctoral training and continued to work on endothelial MEKK3 function in adult stage. I was first to find that endothelial MEKK3 deletion in adult mice develop spontaneous pulmonary and systemic hypertension. Deletion of MEKK3 in adult endothelium resulted in a gradual inward remodeling of both pulmonary and systematic arteries and massive activated TGFβ-Smad2/3 signaling. Endothelial MEKK3 deletion also induced endothelial-to-mesenchymal transition (EndMT) and accelerated progression of atherosclerosis in hyperlipidemic mice [2].
3. Regulation of Smad2/3 by fluid shear stress (FSS): During my postdoctoral training, we found that Smad2/3 nuclear translocation is maximal under low FSS (1-5 dynes/cm2), then decreases as FSS reaches the physiological range (>12 dynes/cm2). Low FSS activates Smad2/3 through ALK5 and co-receptor Nrp1, leading to inward remodeling. Physiological FSS suppresses Smad2/3 by modulating Smad2/3 linker region phosphorylation. This specific phosphorylation is mediated by CDK2, whose activity is controlled by MEKK3-KLF2 signaling axis [3]. Physiological FSS also inhibits endothelial Smad2/3 activation and EndMT in response to inflammatory mediators, indicating region-selective formation and progression of atherosclerotic lesions [4].
4. High fluid shear stress (FSS)-mediated outward artery remodeling: In contrast to Smad2/3, Smad1/5 is maximally activated at physiological FSS and suppressed at higher flow [5]. We found that suppression of Smad1/5 at high FSS is mediated by elevated KLF2, which induces the BMP pathway inhibitor BMPER, which suppresses Smad1/5 and de-inhibits Akt. In a mouse arteriovenous fistula (AVF) model, high FSS induces artery outward remodeling coincident with elevated BMPER expression and Smad1/5 inactivation. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling in the AVF and a hindlimb ischemia (HLI) model, with the latter reversed by BMP9/10 blocking antibodies (bAbs). In both type 1 and type 2 diabetic mice that show poor recovery from HLI, BMP9/10 bAbs improved outcomes [6]. Thus, suppression of Smad1/5 is required for high FSS-mediated outward remodeling and is a potential therapeutic approach for treatment for peripheral vascular disease (PVD) in human.
5. Endothelial cell cycle regulates flow-dependent artery remodeling: We collaborated with Prof. Boris N. Kholodenko (University College Dublin) and used a powerful new computational method, cSTAR, to define EC transcriptomic states under low shear stress (LSS) that triggers vessel inward remodeling, physiological shear stress (PSS) that stabilizes vessels, high shear stress (HSS) that triggers outward remodeling, and oscillatory shear stress (OSS) that confers disease susceptibility. Combined with EC transcriptomic responses to drug treatments from the LINCS database, we defined a regulatory network where OSS and LSS induce distinct inflammatory mediators and cyclin-dependent kinases CDK1/2 play a central role in promoting vessel stability. In vitro, PSS induced late G1 cell cycle arrest with active CDK2. In mice, EC deletion of CDK2 triggered inward artery remodeling, resulted in both pulmonary and systemic hypertension, and accelerated atherosclerosis in hyperlipidemia [7]. These results validate use of cSTAR to determine EC state and in vivo vessel behavior, reveal unexpected features of EC phenotype under different FSS conditions, and identify CDK2 as a key element within EC regulatory network that governs artery remodeling.

References

1. Fisher O^#, Deng H^#, Liu D, Zhang Y, Wei R, Deng Y, Zhang F, Louvi A, Turk B, Boggon T* & Su B*. Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex. Nature Communications. 2015 Aug 3; 6:7937. PubMed PMID: 26235885; PMCID: PMC4526114.
2. Deng H, Xu Y, Hu X, Zhuang Z, Chang Y, Wang Y, Ntokou A, Schwartz MA, Su B, Simons M. MEKK3-TGFβ crosstalk regulates inward arterial remodeling. Proc Natl Acad Sci U S A. 2021 Dec 21;118(51):e2112625118. PubMed PMID: 34911761; PMCID: PMC8713777.
3. Deng H, Min E, Baeyens N, Coon BG, Hu R, Zhuang Z, Chen M, Huang B, Afolabi T, Zarkada G, Acheampong A, McEntee K, Eichmann A, Liu F, Su B, Simons M, Schwartz MA. Activation of Smad2/3 signaling by low fluid shear stress mediates artery inward remodeling. Proc Natl Acad Sci U S A. 2021 Sep 14; 118(37):e2105339118. PubMed PMID: 34504019; PMCID: PMC8449390.
4. Deng H, Schwartz MA. High fluid shear stress inhibits cytokine-driven Smad2/3 activation in vascular endothelial cells. J Am Heart Assoc. 2022 Jul 19;11(14):e025337. PubMed PMID: 35861829. PMCID: PMC9707828.
5. Tiezzi M^#, Deng H^#, Baeyens N. Endothelial mechanosensing: a forgotten target to treat vascular remodeling in hypertension? Biochemical Pharmacology. 2022 Oct 12;206:115290. PubMed PMID: 36241094.
6. Deng H, Zhang J, Wang Y, Joshi D, Pi X, De Val S, Schwartz MA. A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling. Nature Cardiovascular Research. 2024 July 8. DOI: https://doi.org/10.1038/s44161-024-00496-y. PubMed PMID: 39196179.
7. Deng H^#, Rukhlendo OS^#, Joshi D, Hu X, Junk P, Tuliakova A, Kholodenko BN^*, Schwartz MA^*. cSTAR analysis identified endothelial cell cycle as a key regulator of flow-dependent artery remodeling. Science Advances. 2025 Jan 3. PubMed PMID: 39752487. PMCID: PMC11698091. DOI: https://www.science.org/doi/10.1126/sciadv.ado9970.