Travis W. Hein, PhD
Education and Post-Graduate Training
BA, Biology, St. Olaf College, 1992
PhD, Medical Sciences, Texas A&M Health Science Center, 1997
My laboratory studies the regulation of microvascular function at the level of arterioles in the retinal and coronary circulations. Sufficient blood flow supply of oxygen and nutrients to tissues to maintain normal function is controlled in large part by changes in the diameter of arterioles. Vasoconstriction or vasodilation of these small arteries will decrease or increase blood flow and nutrient delivery to the tissue, respectively. Two key chemical factors that are produced within the endothelial cells of blood vessels to control their diameter are nitric oxide (NO), a vasodilator, and endothelin-1, a vasoconstrictor. An imbalance in the production and/or release of these vasoactive factors has been implicated in the early stages of several cardiovascular diseases, but the underlying mechanisms contributing to these pathophysiological changes remain unclear. To address this knowledge gap, our research focuses on identifying cellular and molecular mechanisms that contribute to the vasomotor responses of arterioles to NO and endothelin-1 under conditions of health and disease. Current approaches that we use to investigate these mechanisms in the microcirculation include isolated and perfused arterioles, cultured vascular endothelial and smooth muscle cells, biochemical and molecular techniques (for detection of NO, superoxide anion, protein, and mRNA in arterioles), pharmacological and silencing RNA (siRNA) treatments, and blood flow velocity assessment via Doppler ultrasound.
Emerging evidence supports the paradigm that inflammation plays a pivotal role in the development and progression of vascular disorders such as atherosclerosis and ischemia-reperfusion injury. Our recent studies in the heart have shown that the inflammatory marker C-reactive protein (CRP), which is now established as a cardiovascular risk factor, impairs endothelium-dependent NO-mediated vasodilator function and NO production in coronary arterioles. This arteriolar dysfunction is caused by CRP-induced activation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and subsequent NAD(P)H oxidase-mediated superoxide production. An additional mechanism that may contribute to vasomotor dysfunction includes a reduction in the intracellular levels of L-arginine, the NO precursor, in arterioles. My colleagues and I provided the first evidence that constitutive expression of arginase I, an L-arginine consuming enzyme, in endothelial cells counteracts NO-dependent dilation of coronary arterioles. The results from this study suggest a novel pathway for modulating NO production in coronary microvessels. This basic information was extended to the pathophysiological condition of ischemia and reperfusion (I/R) in the heart where we have shown that upregulation of the vascular arginase I isoform during the I/R insult can impair NO-mediated dilation of coronary arterioles.
Alteration in nutritional blood flow to the retina in the eye and damage to the neural cells are regarded as key events leading to visual impairment and blindness. Although retinal arterioles play a predominant role in regulating optimal retinal blood flow to the neural retina, there is sparse information on how these vessels function under health and disease states. My laboratory has provided new insight into mechanisms contributing to the ability of retinal arterioles to dilate and constrict under normal conditions and pathophysiological states of ischemia, inflammation, and diabetes. We have shown that endogenous metabolic factors (adenosine and lactate) and mechanical stimulus (increased luminal flow/shear stress) cause endothelium-dependent NO-mediated dilation of retinal arterioles. Activation of vascular endothelial growth factor (VEGF) receptor 2 in the endothelium mediates the NO-dependent vasodilations in response to flow. Extending this fundamental information to the disease condition, we have demonstrated that NO-mediated dilation is reduced by acute retinal ischemia and by acute exposure to CRP, which are both prevented by antioxidant treatment. One of our current projects focuses on the impact of early stage diabetes on retinal arteriolar function and we have shown selective impairment of endothelium-dependent NO-mediated vasodilation via activation of the pro-inflammatory c-Jun N-terminal kinase (JNK) signaling pathway.
Enhanced production of endothelin-1 (ET-1) leading to constriction of retinal arterioles and diminished retinal blood flow has been implicated in the development of retinal pathology. Our recent findings provided the first characterization of molecular signaling events contributing to ET-1 system signaling in retinal arterioles. We reported that ET-1 causes constriction of retinal arterioles by stimulating the smooth muscle ETA receptor subtype and subsequent activation of Rho kinase (ROCK). The ET-1-induced ROCK activation depends on extracellular calcium entry but is independent of protein kinase C and L-type voltage-operated calcium channels. Our current studies are investigating the potential molecular source of extracellular calcium entry in retinal arterioles and the potential role of ET-1 in diabetes-induced retinal microvascular dysfunction at the level of both arterioles and venules.
Information gleaned from our studies will help provide a better understanding of vasomotor function of coronary and retinal arterioles and will potentially yield amenable targets for therapies of diseases associated with coronary and/or retinal vascular dysfunction.
- Hein TW, Zhang C, Wang W, Chang CI, Thengchaisri N, Kuo L. Ischemia-reperfusion selectively impairs nitric oxide-mediated dilation in coronary arterioles: counteracting role of arginase. FASEB J. 2003 Dec;17(15):2328-30. doi: 10.1096/fj.03-0115fje. PMID:14563685
- Qamirani E, Wang W, Kuo L, Hein TW. C-reactive protein inhibits endothelium-dependent NO-mediated dilation in coronary arterioles by activating p38 kinase and NAD(P)H oxidase. Arterioscler Thromb Vasc Biol. 2005 May;25(5):995-1001. doi: 10.1161/01.ATV.0000159890.10526.1e.PMID: 15718491
- Hein TW, Yuan Z, Rosa RH Jr, Kuo L. Requisite roles of A2A receptors, nitric oxide, and KATP channels in retinal arteriolar dilation in response to adenosine. Invest Ophthalmol Vis Sci. 2005 Jun;46(6):2113-9. doi: 10.1167/iovs.04-1438. PMID: 15914631
- Hein TW, Ren Y, Yuan Z, Xu W, Somvanshi S, Nagaoka T, Yoshida A, Kuo L. Functional and molecular characterization of the endothelin system in retinal arterioles. Invest Ophthalmol Vis Sci. 2009 Jul;50(7):3329-36. doi: 10.1167/iovs.08-3129. PMID: 19151386; PMCID: PMC2761152
- Hein TW, Rosa RH Jr, Yuan Z, Roberts E, Kuo L. Divergent roles of nitric oxide and phosphoinositide 3-kinase/Rho kinase in vasoreactivity of human retinal arterioles. Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1583-90. doi: 10.1167/iovs.09-4391. PMID: 19850828; PMCID: PMC2868420
- Potts LB, Ren Y, Lu G, Kuo E, Ngo E, Kuo L, Hein TW. Constriction of retinal arterioles to endothelin-1: Requisite role of Rho kinase independent of protein kinase C and L-type calcium channels. Invest Ophthalmol Vis Sci. 2012 May 17;53(6):2904-12. doi: 10.1167/iovs.12-9542. PMID: 22427601; PMCID: PMC3376072
- Hein TW, Potts LB, Xu W, Yuen JZ, Kuo L. Temporal development of retinal arteriolar endothelial dysfunction in porcine type 1 diabetes. Invest Ophthalmol Vis Sci. 2012 Dec 3;53(13):7943-9. doi: 10.1167/iovs.12-11005. PMID: 23139282; PMCID: PMC3513275
- Hein TW, Qamirani E, Ren Y, Xu X, Thengchaisri N, Kuo L. Selective activation of lectin-like oxidized low-density lipoprotein receptor-1 mediates C-reactive protein-evoked endothelial vasodilator dysfunction in coronary arterioles. Circ Res. 2014 Jan 3;114(1):92-100. doi: 10.1161/CIRCRESAHA.114.301763. PMID: 24141169
- Hein TW, Rosa RH Jr, Ren Y, Xu W, Kuo L. VEGF Receptor-2-linked PI3K/calpain/SIRT1 activation mediates retinal arteriolar dilations to VEGF and shear stress. Invest Ophthalmol Vis Sci. 2015 Aug;56(9):5381-9. doi: 10.1167/iovs15-16950. PMID: 26284543; PMCID: PMC4544352
- Hein TW, Xu W, Xu X, Kuo L. Acute and chronic hyperglycemia elicit JIP1/JNK-mediated endothelial vasodilator dysfunction of retinal arterioles. Invest Ophthalmol Vis Sci. 2016 Aug 1;57(10):4333-40. doi: 10.1167/iovs.16-19990. PMID: 27556216; PMCID: PMC5015966
- Chen YL, Ren Y, Xu W, Rosa RH Jr, Kuo L, Hein TW. Constriction of retinal venules to endothelin-1: Obligatory roles of ETA receptors, extracellular calcium entry, and Rho kinase. Invest Ophthalmol Vis Sci. 2018 Oct 1;59(12):5167-5175. doi: 10.1167/iovs.18-25369. PMID: 30372743; PMCID: PMC6203175