Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Angiogenesis
Published in: Angiogenesis 1/2015

01-01-2015 | Original Paper

Genetic variation in retinal vascular patterning predicts variation in pial collateral extent and stroke severity

Authors: Pranay Prabhakar, Hua Zhang, De Chen, James E. Faber

Published in: Angiogenesis | Issue 1/2015

Login to get access

Abstract

The presence of a native collateral circulation in tissues lessens injury in occlusive vascular diseases. However, differences in genetic background cause wide variation in collateral number and diameter in mice, resulting in large variation in protection. Indirect estimates of collateral perfusion suggest that wide variation also exists in humans. Unfortunately, methods used to obtain these estimates are invasive and not widely available. We sought to determine whether differences in genetic background in mice result in variation in branch patterning of the retinal arterial circulation, and whether these differences predict strain-dependent differences in pial collateral extent and severity of ischemic stroke. Retinal patterning metrics, collateral extent, and infarct volume were obtained for 10 strains known to differ widely in collateral extent. Multivariate regression was conducted, and model performance was assessed using K-fold cross-validation. Twenty-one metrics varied with strain (p < 0.01). Ten metrics (e.g., bifurcation angle, lacunarity, optimality) predicted collateral number and diameter across seven regression models, with the best model closely predicting (p < 0.0001) number (±1.2–3.4 collaterals, K-fold R 2 = 0.83–0.98), diameter (±1.2–1.9 μm, R 2 = 0.73–0.88), and infarct volume (±5.1 mm3, R 2 = 0.85–0.87). An analogous set of the most predictive metrics, obtained for the middle cerebral artery (MCA) tree in a subset of the above strains, also predicted (p < 0.0001) collateral number (±3.3 collaterals, K-fold R 2 = 0.78) and diameter (±1.6 μm, R2  = 0.86). Thus, differences in arterial branch patterning in the retina and the MCA trees are specified by genetic background and predict variation in collateral extent and stroke severity. If also true in human, and since genetic variation in cerebral collaterals extends to other tissues at least in mice, a similar “retinal predictor index” could serve as a non- or minimally invasive biomarker for collateral extent in brain and other tissues. This could aid prediction of severity of tissue injury in the event of an occlusive event or development of obstructive disease and in patient stratification for treatment options and clinical studies.
Appendix
Available only for authorised users
Literature
1.
Shuaib A, Butcher K, Mohammad AA, Saqqur M, Liebeskind DS (2011) Collateral blood vessels in acute ischaemic stroke: a potential therapeutic target. Lancet Neurol 10:909–921PubMedCrossRef
2.
Meier P, Hemingway H, Lansky AJ, Knapp G, Pitt B, Seiler C (2012) The impact of the coronary collateral circulation on mortality: a meta-analysis. Eur Heart J 33:614–621PubMedCrossRef
3.
Zhang H, Prabhakar P, Sealock RW, Faber JE (2010) Wide genetic variation in the native pial collateral circulation is a major determinant of variation in severity of stroke. J Cerebral Blood Flow Metab 30:923–934CrossRef
4.
5.
Christoforidis GA, Karakasis C, Mohammad Y, Caragine LP, Yang M, Slivka AP (2009) Predictors of hemorrhage following intra-arterial thrombolysis for acute ischemic stroke: the role of pial collateral formation. AJNR Am J Neuroradiol 30:165–170PubMedCrossRef
6.
Miteff F, Levi CR, Bateman GA, Spratt N, McElduff P, Parsons MW (2009) The independent predictive utility of computed tomography angiographic collateral status in acute ischaemic stroke. Brain 132:2231–2238PubMedCrossRef
7.
Lima FO, Furie KL, Silva GS, Lev MH, Camargo EC, Singhal AB, Harris GJ, Halpern EF, Koroshetz WJ, Smith WS, Yoo AJ, Nogueira RG (2010) The pattern of leptomeningeal collaterals on CT angiography is a strong predictor of long-term functional outcome in stroke patients with large vessel intracranial occlusion. Stroke 41:2316–2322PubMedCrossRef
8.
Jung S, Gilgen M, Slotboom J, El-Koussy M, Zubler C, Kiefer C, Luedi R, Mono ML, Heldner MR, Weck A, Mordasini P, Schroth G, Mattle HP, Arnold M, Gralla J, Fischer U (2013) Factors that determine penumbral tissue loss in acute ischaemic stroke. Brain 136:3554–3560PubMedCrossRef
9.
Nambiar V, Sohn SI, Almekhlafi MA, Chang HW, Mishra S, Qazi E, Eesa M, Demchuk AM, Goyal M, Hill MD, Menon BK (2014) Collateral status and response to recanalization in patients with acute ischemic stroke. AJNR Am J Neuroradiol 35:884–890PubMedCrossRef
10.
Meier P, Gloekler S, Zbinden R, Beckh S, de Marchi SF, Zbinden S, Wustmann K, Billinger M, Vogel R, Cook S, Wenaweser P, Togni M, Windecker S, Meier B, Seiler C (2007) Beneficial effect of recruitable collaterals: a 10-year follow-up study in patients with stable coronary artery disease undergoing quantitative collateral measurements. Circulation 116:975–983PubMedCrossRef
11.
Traupe T, Ortmann J, Stoller M, Baumgartner I, de Marchi SF, Seiler C (2013) Direct quantitative assessment of the peripheral artery collateral circulation in patients undergoing angiography. Circulation 128:737–744PubMedCrossRef
12.
Wang S, Zhang H, Wiltshire T, Sealock R, Faber JE (2012) Genetic dissection of the Canq1 locus governing variation in extent of the collateral circulation. PLoS One 7:31910CrossRef
13.
Keum S, Marchuk DA (2009) A locus mapping to mouse chromosome 7 determines infarct volume in a mouse model of ischemic stroke. Circ Cardiovasc Genet 2:591–598PubMedCentralPubMedCrossRef
14.
Sealock R (2014) Zhang, Lucitti J, Moore S, Faber J. Congenic fine-mapping identifies a major causal locus for variation in the native collateral circulation and ischemic injury in brain and lower extremity. Circ Res 114:660–671PubMedCrossRef
15.
Lee Y, Menon B, Huang D, Wilhelmsen K, Jovin T, Parsons M, Ribo M, Selim M, Sheth K, Al-Ali F, Marshall R, Shuaib A, Demchuk A, Powers W, Liebeskind D, Faber J (2014) GENEtic Determinants of Collateral Status in Stroke—The GENEDCSS Study. AHA/ASA International Stroke Conference
16.
Chalothorn D, Faber JE (2010) Formation and maturation or the murine native cerebral collateral circulation. J Molec Cell Cardiol 49:251–259CrossRef
17.
Lucitti JL, Mackey J, Morrison JC, Haigh JJ, Adams RH, Faber JE (2012) Formation of the collateral circulation is regulated by vascular endothelial growth factor-A and A disintegrin and metalloprotease family members 10 and 17. Circ Res 111:1539–1550PubMedCentralPubMedCrossRef
18.
Chalothorn D, Clayton JA, Zhang H, Pomp D, Faber JE (2007) Collateral density, remodeling and VEGF-A expression differ widely between mouse strains. Physiol Genomics 30:179–191PubMedCrossRef
19.
Clayton JA, Chalothorn D, Faber JE (2008) Vascular endothelial growth factor-A specifies formation of native collaterals and regulates collateral growth in ischemia. Circ Res 103:1027–1036PubMedCentralPubMedCrossRef
20.
Chalothorn D, Zhang H, Smith JE, Edwards JC, Faber JE (2009) Chloride intracellular channel-4 is a determinant of native collateral formation in skeletal muscle and brain. Circ Res 105:89–98PubMedCentralPubMedCrossRef
21.
Dai X, Faber JE (2010) eNOS deficiency causes collateral vessel rarefaction and impairs activation of a cell cycle gene network during arteriogenesis. Circ Res 106:1870–1881PubMedCentralPubMedCrossRef
22.
MacGabhann F, Peirce SM (2010) Collateral capillary arterialization following ligation in murine skeletal muscle. Microcirc. 17:333–347
23.
Moore SM, Waters MR, Faber JE (2013) Hypertension and other cardiovascular risk factors lead to premature rarefaction of the native collateral circulation. J Vasc Surg 57(5):79CrossRef
24.
Liew G, Wang JJ, Mitchell P, Wong TY (2008) Retinal vascular imaging. Circ Cardiovasc Imaging 1:156–161PubMedCrossRef
25.
Patton N, Aslam T, MacGillivray T, Pattie A, Deary IJ, Dhillon B (2005) Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures. J Anat 206:319–348PubMedCentralPubMedCrossRef
26.
Witt N, Wong TY, Hughes AD, Chaturvedi N, Klein BE, Evans R, McNamara M, Thom SA, Klein R (2006) Abnormalities of retinal microvascular structure and risk of mortality from ischemic heart disease and stroke. Hypertension 47:975–981PubMedCrossRef
27.
Patton N, Aslam TM, MacGillivray T, Deary IJ, Dhillon B, Eikelboom RH, Yogesan K, Constable IJ (2006) Retinal image analysis: concepts, applications and potential. Prog Retin Eye Res 25:99–127PubMedCrossRef
28.
Hughes AD, Wong TY, Witt N, Evans R, Thom SA, Klein BE, Chaturvedi N, Klein R (2009) Determinants of retinal microvascular architecture in normal subjects. Microcirculation 16:159–166PubMedCrossRef
29.
Witt NW, Chapman N, Thom SA, Stanton AV, Parker KH, Hughes AD (2010) A novel measure to characterize optimality of diameter relationships at retinal vascular bifurcations. Artery Res 4:75–80PubMedCentralPubMedCrossRef
30.
Knudtson MD, Lee KE, Hubbard LD, Wong TY, Klein R, Klein BE (2003) Revised formulas for summarizing retinal vessel diameters. Curr Eye Res 27:143–149PubMedCrossRef
31.
Arganda-Carreras I, Fernandez-Gonzalez R, Munoz-Barrutia A, Ortiz-De-Solorzano C (2010) 3D reconstruction of histological sections: application to mammary gland tissue. Microsc Res Tech 73:1019–1029PubMedCrossRef
32.
Steyerberg E (2009) Validation of prediction models. In: clinical prediction models. Springer Science + Business Media, LLC. Chapter 17, pp 299–311
33.
Doubal FN, MacGillivray TJ, Patton N, Dhillon B, Dennis MS, Wardlaw JM (2010) Fractal analysis of retinal vessels suggests that a distinct vasculopathy causes lacunar stroke. Neurology 74:1102–1107PubMedCentralPubMedCrossRef
34.
Cristofaro B, Shi Y, Faria M, Suchting S, Leroyer AS, Trindade A, Duarte A, Zovein AC, Iruela-Arispe ML, Nih LR, Kubis N, Henrion D, Loufrani L, Todiras M, Schleifenbaum J, Gollasch M, Zhuang ZW, Simons M, Eichmann A, le Noble F (2013) Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models. Development 140:1720–1729PubMedCentralPubMedCrossRef
35.
Saint-Geniez M, D’Amore PA (2004) Development and pathology of the hyaloid, choroidal and retinal vasculature. Int J Dev Biol 48:1045–1058PubMedCrossRef
36.
37.
Gielecki J, Zurada A, Kozłowska H, Nowak D, Loukas M (2009) Morphometric and volumetric analysis of the middle cerebral artery in human fetuses. Acta Neurobiol Exp (Wars) 69:129–137
38.
Okudera T, Ohta T, Huang YP, Yokota A (1988) Developmental and radiological anatomy of the superficial cerebral convexity vessels in the human fetus. J Neuroradiol 15:205–224PubMed
39.
Provis JM (2001) Development of the primate retinal vasculature. Prog Ret Eye Res. 20:799–821CrossRef
40.
Fielder AR, Quinn GE (2005) Retinopathy of prematurity (chapter 51). In: Taylor D, Hoyt CS (eds) Pediatric ophthalmology and strabismus, 3rd edn. Elsevier Saunders, Edinburgh, pp 506–530
41.
Faber JE, Dai X, Lucitti J (2011) Genetic and environmental mechanisms controlling formation and maintenance of the native collateral circulation ch 1. In: Deindl IE, Schaper W (eds) Arteriogenesis—molecular regulation, pathophysiology and therapeutics. Shaker Verlag, Aachen, pp 1–22
42.
Fahy SJ, Sun C, Zhu G, Healey PR, Spector TD, Martin NG, Mitchell P, Wong TY, Mackey DA, Hammond CJ, Andrew T (2011) The relationship between retinal arteriolar and venular calibers is genetically mediated, and each is associated with risk of cardiovascular disease. Invest Ophthalmol Vis Sci 52:975–981PubMedCentralPubMedCrossRef
43.
Taarnhoj NC, Larsen M, Sander B, Kyvik KO, Kessel L, Hougaard JL, Sørensen TI (2006) Heritability of retinal vessel diameters and blood pressure: a twin study. Invest Opthalmol Vis Sci 47:3539–3544CrossRef
44.
Lee KE, Klein BE, Klein R, Knudtson MD (2004) Familial aggregation of retinal vessel caliber in the beaver dam eye study. Invest Ophthalmol Vis Sci 45:3929–3933PubMedCrossRef
45.
Liu YP, Kuznetsova T, Jin Y, Thijs L, Asayama K, Gu YM, Bochud M, Verhamme P, Struijker-Boudier HA, Staessen JA (2013) Heritability of the retinal microcirculation in Flemish families. Am J Hypertens 26:392–399PubMedCentralPubMedCrossRef
46.
Taarnhoj NC, Munch IC, Sander B, Kessel L, Hougaard JL, Kyvik K, Sørensen TI, Larsen M (2008) Straight versus tortuous retinal arteries in relation to blood pressure and genetics. Br J Ophthalmol 92:1055–1060PubMedCrossRef
47.
Ikram MK, Sim X, Jensen RA, Cotch MF, Hewitt AW, Ikram MA, Wang JJ, Klein R, Klein BE, Breteler MM, Cheung N, Liew G, Mitchell P, Uitterlinden AG, Rivadeneira F, Hofman A, de Jong PT, van Duijn CM, Kao L, Cheng CY, Smith AV, Glazer NL, Lumley T, McKnight B, Psaty BM, Jonasson F, Eiriksdottir G, Aspelund T, Global BPgen Consortium, Harris TB, Launer LJ, Taylor KD, Li X, Iyengar SK, Xi Q, Sivakumaran TA, Mackey DA, Macgregor S, Martin NG, Young TL, Bis JC, Wiggins KL, Heckbert SR, Hammond CJ, Andrew T, Fahy S, Attia J, Holliday EG, Scott RJ, Islam FM, Rotter JI, McAuley AK, Boerwinkle E, Tai ES, Gudnason V, Siscovick DS, Vingerling JR, Wong TY (2010) Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. PLoS Genet 6:e1001184PubMedCentralPubMedCrossRef
48.
Wong TY, Klein R, Couper DJ, Cooper LS, Shahar E, Hubbard LD, Wofford MR, Sharrett AR (2001) Retinal microvascular abnormalities and incident stroke: the atherosclerosis risk in communities study. Lancet 358(9288):1134–1140PubMedCrossRef
49.
Doubal FN, Hokke PE, Wardlaw JM (2009) Retinal microvascular abnormalities and stroke: a systematic review. J Neurol Neurosurg Psychiatr 80:158–165PubMedCrossRef
50.
Lindley RI, Wang JJ, Wong M, Mitchell P, Liew G, Hand P, Wardlaw J, De Silva DA, Baker M, Rochtchina E, Chen C, Hankey GJ, Chang HM, Fung VS, Gomes L, Wong TY (2009) Retinal microvasculature in acute lacunar stroke: a cross-sectional study. Lancet Neurol 8:628–634PubMedCrossRef
51.
Kwa VI, Lopez OL (2010) Fractal analysis of retinal vessels: peeping at the tree of life? Neurology 74:1088–1089PubMedCrossRef
52.
Faber JE, Zhang H, Lassance-Soares RM, Prabhakar P, Najafi AH, Burnett MS, Epstein SE (2011) Aging causes collateral rarefaction and increased severity of ischemic injury in multiple tissues. Arterioscler Thromb Vasc Biol 31:1748–1756PubMedCentralPubMedCrossRef
53.
Menon BK, Smith EE, Coutts SB, Welsh DG, Faber JE, Damani Z, Goyal M, Hill MD, Demchuk AM, Hee Cho K-H, Chang H-W, Hong J-H, Sohn SI (2013) Leptomeningeal collaterals are associated with modifiable metabolic risk factors. Ann Neurol 74:241–248PubMedCentralPubMed
54.
Threadgill DW, Miller DR, Churchill GA, de Villena FP (2011) The collaborative cross: a recombinant inbred mouse population for the systems genetic era. ILAR J 52:24–31PubMedCrossRef
55.
Smolock EM, Ilyushkina IA, Ghazalpour A, Gerloff J, Murashev AN, Lusis AJ, Korshunov VA (2012) Genetic locus on mouse chromosome 7 controls elevated heart rate. Physiol Genomics 44:689–698PubMedCentralPubMedCrossRef
56.
Stanton AV, Wasan B, Cerutti A, Ford S, Marsh R, Sever PP, Thom SA, Hughes AD (1995) Vascular network changes in the retina with age and hypertension. J Hypertens 13:1724–1728PubMedCrossRef
57.
de Marchi SF, Gloekler S, Meier P, Traupe T, Steck H, Cook S, Vogel R, Seiler C (2011) Determinants of preformed collateral vessels in the human heart without coronary artery disease. Cardiology 118:198–206PubMedCrossRef
58.
Vickerman MB, Keith PA, McKay TL, Gedeon DJ, Watanabe M, Montano M, Karunamuni G, Kaiser PK, Sears JE, Ebrahem Q, Ribita D, Hylton AG, Parsons-Wingerter P (2009) VESGEN 2D: automated, user-interactive software for quantification and mapping of angiogenic and lymphangiogenic trees and networks. Anat Rec (Hoboken) 292:320–332PubMedCentralCrossRef
59.
Cheung CY, Hsu W, Lee ML, Wang JJ, Mitchell P, Lau QP, Hamzah H, Ho M, Wong TY (2010) A new method to measure peripheral retinal vascular caliber over an extended area. Microcirculation 17:495–503PubMed
60.
Calleja AI, Cortijo E, García-Bermejo P, Gómez RD, Pérez-Fernández S, Del Monte JM, Muñoz MF, Fernández-Herranz R, Arenillas JF (2013) Collateral circulation on perfusion-computed tomography-source images predicts the response to stroke intravenous thrombolysis. Eur J Neurol 20:795–802PubMedCrossRef
61.
Wang S, Zhang H, Dai X, Sealock R, Faber JE (2010) Genetic architecture underlying variation in extent and remodeling of the collateral circulation. Circ Res 107:558–568PubMedCentralPubMedCrossRef
Metadata
Title
Genetic variation in retinal vascular patterning predicts variation in pial collateral extent and stroke severity
Authors
Pranay Prabhakar
Hua Zhang
De Chen
James E. Faber
Publication date
01-01-2015
Publisher
Springer Netherlands
Published in
Angiogenesis / Issue 1/2015
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI
https://doi.org/10.1007/s10456-014-9449-y

Other articles of this Issue 1/2015

Angiogenesis 1/2015 Go to the issue

Original Paper

Angiogenesis and airway reactivity in asthmatic Brown Norway rats

Original Paper

Segregation of late outgrowth endothelial cells into functional endothelial CD34− and progenitor-like CD34+ cell populations

Original Paper

Contrast-enhanced molecular ultrasound differentiates endoglin genotypes in mouse embryos

Original Paper

Inhibition of tumor-associated αvβ3 integrin regulates the angiogenic switch by enhancing expression of IGFBP-4 leading to reduced melanoma growth and angiogenesis in vivo

Original Paper

Robo4 vaccines induce antibodies that retard tumor growth

Original Paper

The carboxyl terminus of VEGF-A is a potential target for anti-angiogenic therapy
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits