Funded primarily by the NIH/NHLBI and AHA, the AVML group has made some important discoveries that:

(a) Delineated the mechanisms by which fluid mechanical forces/shear stress reg­ulates throm­bosis/thrombolysis and inflammation on the vessel wall (papers published in the period 1998-2012);

(b) Provided the first evidence that fluid shear stress initiates reactive oxy­gen species (ROS)-mediated signaling inside vascular endothelial cells (ECs) and investigated the mech­anisms leading to shear-induced EC ROS production (papers published in the period 1999-2001);

(c) Delineated the path­ways by which ROS in­crease leukocyte adhesion (inflammation) to post-hypoxic ECs, and the mech­a­nisms by which simulated ischemia leads to EC damage (papers published in the period 2002-2005);

(d) Provided the first evi­dence that fluid shear stress affects EC mitochondrial respi­ration and mitochondrial ROS (mROS) production and that the EC mitochondrial redox state coor­di­nates shear-induced gene expres­sion (papers published in the period 2007-2011);

(e) Delin­eated the molecular mecha­nisms by which simulated ischemia/reperfusion (I/RP) leads to mROS generation and EC dysfunction, and the role of bi­o­ener­get­ics in mito­chondrial network morphology/motility, which may determine EC survival (papers published in the period 2012-2014);

(f) Character­ized the dy­namic changes in intracellular Ca2+ concentration ([Ca2+]i) in sheared ECs, and provided the first evidence that the shear-induced [Ca2+]i response is regulated by the mitochondrial Ca2+ uptake/transport by the Mitochondrial Ca2+ Uniporter (MCU) channel (papers published in the period 2016-2019).


Research project 1:
Mitochondrial Ca2+– and ROS-mediated signaling in ECs exposed to mechanical forces (shear stress or pressure)

A major part of our current work focuses on investigating the role of mitochon­dria in regulating Ca2+ and ROS signaling in cultured ECs exposed to defined fluid me­chan­ical forces. EC expo­sure to arterial-level, either steady laminar shear stress (SS) or pulsatile laminar shear stress (PS), is known to cause an increase in [Ca2+]i due to endo­plasmic reticulum (ER) Ca2+ release and extracellu­lar Ca2+ influx. Shear stress, via the [Ca2+]i increase, activates the endothelial nitric oxide synthase (eNOS) that produces the vaso­dilator nitric oxide (NO). NO regulates the vascular tone and maintains an anti-inflam­matory/anti-thrombotic vessel wall. It is known that local hemodynamic forces modulate the EC phenotype, and this phe­notypic modu­lation contributes to the focal nature of atherosclerotic disease (Fig. 1). ECs in OS-exposed (athero­prone) arterial regions experience higher ROS levels and ex­hibit inflammation and increased sensitization to apoptosis compared to ECs in PS-exposed (athero­protective) regions. In collaboration with Dr. Madesh Muniswamy, University of Texas Health San Antonio, we showed that Ca2+ uptake by the mitochondria, via the MCU channel, is critical for the shear-induced EC Ca2+ signaling, and hypothesized that EC exposure to different flow profiles may differentially regulate the MCU complex protein expression/activity. OS-induced changes in mitochondrial Ca2+ transport may be, at least in part, responsible for the EC dysfunction and initiation of atherosclerotic disease. Understanding these signaling pathways may lead to development of endothelial-targeted therapeutics for preven­tion and/or treatment of coronary artery disease/heart disease. Similarly, we are interested in understanding the effects of short-term increases in intraluminal pressure (in the context of heart failure with preserved ejection fraction; HFpEF) on Ca2+/ROS signaling and EC function, in collaboration with Drs. John M. Canty and Brian R. Weil, UB Jacobs School of Medicine and Biomedical Sciences.

Fig. 1. Shear stress on vascular endothelium. (a) Axial velocities at different locations in a bifurca­tion, such as the carotid, coro­nary, renal, and iliac artery flow dividers. Regions ex­posed to PS (blue circles) are spared from athero­sclerosis, whereas those exposed to OS (yellow circles) are prone to disease. (b) Idealized shear stress profiles shown for PS, SS, OS, and static controls (Alevriadou et al. J R Soc Interface, 2017;

Research project 2:
Regulatory mechanisms of gene/protein expression in ECs exposed to mechanical forces

Our earlier studies have shown that shear-induced changes in ROS, mROS, and intracellular and mitochondrial Ca2+ levels can drive (patho)physiological EC signaling. We discovered that SS-induced mROS initiate “protective” signaling that leads to transcriptional activation of the heme oxygenase-1 (HO-1) gene and resultant protein expression (Fig. 2). “Omics” approaches for profiling of the EC genome, transcriptome, miR-nome, DNA methylome, and metabolome, by different groups provided a better understanding of the pathophysiology of atherosclerosis development, as well as opportunities to identify novel molecular targets. In collaboration with Drs. Tom Begley, University at Albany-SUNY, and J. Andres Melendez, SUNY Polytechnic Institute, we are investigating whether the epitranscriptome, which involves RNA modifications that can regulate translation, also plays a role in the OS-induced EC dysfunction and atherosclerotic disease initiation. As a first step, we focus on alkylation repair homolog 8 (ALKBH8), an epitranscriptomic writer with transfer RNA (tRNA) methyltransferase activity that methylates the wobble uridine (U) of selenocysteine (Sec) tRNA to promote the specialized translation, via stop codon recoding, of Sec-containing proteins. ALKBH8 is required for the expression of Sec-containing ROS-detoxifying enzymes that belong to the glutathione peroxidase (GPx1, GPx3, GPx6, GPx4) and thioredoxin reductase (TrxR1) families.

Fig. 2. Shear-induced NO-mediated formation of mitochondrial H2O2 initiates intracellular signaling that leads to upregulation of the antioxidant gene/protein heme oxygenase (HO)-1 (Han et al. J Pharmacol Exp Ther, 2009;

Research Project 3:
Role of aging on EC mitochondrial function, signaling, and survival in response to oxidative stimuli/environments

Many of the medical conditions that predispose to EC dysfunction are typical in the elderly, and aging by itself is considered a key factor in cardiovascular disease development (Fig. 3). Senescent (old) ECs were reported by others to exhibit quantitatively different [Ca2+]i responses to chemical stimuli compared to young ECs. Mitochondrial quality control, such as mitophagy, was also found to be affected by senescence in cultured fibroblasts. In collaboration with Dr. Stelios Andreadis, UB Chemical and Biological Engineering, we are investigating the role of mitochondrial Ca2+ and ROS in cell function/survival of young vs. senescent ECs exposed to defined mechanochemical environments. MCU expression/activity changes with aging may play a role in decreasing the EC’s apoptotic threshold under oxidative stress. By unveiling these age-related changes and their consequences, our work will further advance the understanding of endothelial biology and may lead to development of drugs that will specifically target and protect senescent ECs in atheroprone arterial regions.

Fig. 3. Aging, among other factors, induces dysfunction of the vascular endothelium. Dysfunctional ECs produce higher amounts of the super­oxide radical and other ROS, and lower amounts of NO, compared to healthy ECs. EC dysfunction is the key step in the initiation of atherosclerosis and cardiovascular disease (modified from

Research Project 4:
Extracellular vesicle (EV)-mediated communication among ECs, cardiomyocytes, and leukocytes in health and disease

Different types of cells in the heart, such as ECs, cardiomyocytes, and macrophages, communicate indirectly via extracellular vesicles (EVs), a heterogeneous group of small membrane vesicles, including exosomes, that contain lipids, proteins, and nucleic acids. Since mitochondrial components are found in EVs, EVs comprise the intercellular pathway of mitochondrial quality control, in addition to intracellular pathways which include mitochondrial biogenesis, mitochondrial dynamics (Fig. 4), and mitophagy. Mitochondrial damage was shown by others to increase the number of EC-released EVs. Atheroprone flow was also found to increase the number of EC-released EVs, whereas atheroprotective flow decreased those numbers; the latter effect was mediated by SIRT1/eNOS. In collaboration with Drs. Jennifer K. Lang and John M. Canty, UB Jacobs School of Medicine and Biomedical Sciences, our group is interested in delineating the role of the mechanochemical environment on the numbers and cargo of EC-secreted EVs, and their autocrine and paracrine effects upon cardiac and blood cells. In collaboration with Dr. Jennifer K. Lang, we are also interested in studying the effects of exosomes released by cardiosphere-derived cells (CDCs, a cardiac progenitor cell type) on inflammation (EC-leukocyte adhesive interactions). CDC-released exosomes are known to stimulate angiogenesis, induce cardiomyocyte proliferation/inhibit apoptosis and hypertrophy, and improve cardiac function following injury; they are considered the most promising choice for future cardiac regenerative medicine.

Fig. 4. EC mitochondrial dynamics. (a) Video showing an EC transduced with mito-GFP was acquired for 90 s; only the 0 and 90 s time frames with a cropped region inset are shown. Digital image processing identified all mitochondrial objects (b) and those objects that underwent fission or fusion (c) in the region of interest in 10 s intervals. Inte­racting objects were identi­fied by identical colors, and arrows and arrowheads were added to show fis­sion and fusion events, respectively (Giedt et al. Annals Biomed Eng, 2012;


  • The National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
    • R29HL054089
    • R01HL067027
    • R21HL091417
    • R21HL106392
    • R01HL142673
  • The American Heart Association (AHA)
    • 16GRNT27210014
    • AHA Predoctoral Fellowship (Giedt)
  • State Funds
    • SUNY Empire Innovation Program (EIP)
    • SUNY Promoting Recruitment, Opportunity, Diversity, Inclusion and Growth (PRODiG) Initiative
  • Foundations
    • Whitaker Foundation research grant award
    • Howard Hughes Medical Institute (HHMI) MED into GRAD Predoctoral Fellowship (Scheitlin)