Occlusive vascular disease of the heart, brain and peripheral limbs is the primary cause of morbidity and mortality in the US. Native (pre-existing) collaterals (COLs) interconnect adjacent arterial trees and function critically as bypass vessels i vascular obstruction occurs. Over the past 25 years investigators have focused on mechanisms mediating outward remodeling of COLs in ischemic disease. However, until our work nothing was known about what controls the number and diameter (extent) of these unique vessels in healthy tissue. We have shown that COL extent in murine brain and hindlimb varies widely due to genetic polymorphisms. Moreover, variation in extent has a greater impact on the severity of ischemic tissue injury than does variation in remodeling. Our findings have thus focused attention on the importance of under-standing the genetic mechanisms controlling extent of the native COL circulation. A major goal of the present proposal is to determine if environmental factors, ie, cardiovascular risk factors and disease (CVRFs), also adversely affect COL extent. While observations in patients suggest this could be true, our preliminary studies in mice strongly support this novel hypothesis: Aging causes an age-dose-dependent decline in COL density and diameter (rarefaction) that mechanistically links to endothelial cell/eNOS dysfunction (ECdys)-thus identifying eNOS- NO as an essential maintenance factor for COLs. In other preliminary studies we have found that COLs have remarkable structural and functional specializations, compared to arterioles in the general circulation, e.g., a flow-oriented EC alignment, abundant primary cilia (PRC), increased basal proliferation, and a unique gene expression profile. We hypothesize that this novel COL phenotype reflects the disturbed shear stress (DSS) environment in which COLs reside and is essential for their persistence. Furthermore, we postulate that this DSS environment causes accelerated proliferative EC senescence, and thus high susceptibility of COLs to premature rarefaction by CVRFs.
Aim I will determine if genetic mouse models of CVRFs cause COL rarefac- tion in brain and hindlimb, leading to more severe ischemic tissue injury.
AIM II will test the hypothesis that COL ECs express a unique phenotype, important for their persistence in a DSS environment and sensitivity to rarefaction by CVRFs, using in-depth cellular and molecular analyses, and conditional cell-specific gene targeting.
Aim III will seek to prevent or arrest COL rarefaction in CVRF models using therapies that target EC/eNOS-dysfunction and vascular inflammation that are already in use patients or in clinical trials for other indications. Successful outcome of thes studies will define a new risk factor for ischemic disease-severity, ie, COL rarefaction, and therapeutic approaches to prevent it, and identify a novel structural/gene expression phenotype or marker that distinguishes collaterals from other vessels and which is essential for their persistence and function.

Public Health Relevance

While occlusive vascular disease of the heart, brain and peripheral limbs is the primary cause of morbidity and mortality in the US, native (pre-existing) collaterals that interconnect adjacent arterial trees provide the first line of defense by acting a endogenous bypass vessels when occlusive disease strikes. Our work, which has discovered that the abundance of collaterals varies widely in healthy mice-resulting in a greatly increased risk-severity for ischemic tissue injury in low-extent individuals-has found support in recent human studies. While we have identified genetic polymorphisms that contribute strongly to this variation, our preliminary studies suggest that cardiovascular risk factors, such as aging and hypertension, also greatly diminish collateral extent-leading to this proposal to: 1) test this hypothesis, 2) define the responsible mechanisms, and 3) identify potential preventive therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111070-02
Application #
8551687
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2012-09-26
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$452,314
Indirect Cost
$154,739
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Faber, James E; Moore, Scott M; Lucitti, Jennifer L et al. (2017) Sex Differences in the Cerebral Collateral Circulation. Transl Stroke Res 8:273-283
(2017) 19th Workshop of the International Stroke Genetics Consortium, April 28-29, 2016, Boston, Massachusetts, USA: 2016.001 MRI-defined cerebrovascular genomics-The CHARGE consortium. Neurol Genet 3:S2-S11
Lucitti, Jennifer L; Sealock, Robert; Buckley, Brian K et al. (2016) Variants of Rab GTPase-Effector Binding Protein-2 Cause Variation in the Collateral Circulation and Severity of Stroke. Stroke 47:3022-3031
Prabhakar, Pranay; Zhang, Hua; Chen, De et al. (2015) Genetic variation in retinal vascular patterning predicts variation in pial collateral extent and stroke severity. Angiogenesis 18:97-114
Moore, Scott M; Zhang, Hua; Maeda, Nobuyo et al. (2015) Cardiovascular risk factors cause premature rarefaction of the collateral circulation and greater ischemic tissue injury. Angiogenesis 18:265-81
Zhang, Hua; Faber, James E (2015) De-novo collateral formation following acute myocardial infarction: Dependence on CCR2? bone marrow cells. J Mol Cell Cardiol 87:4-16
Elsherif, Laila; Ozler, Mehmet; Zayed, Mohamed A et al. (2014) Potential compensation among group I PAK members in hindlimb ischemia and wound healing. PLoS One 9:e112239
Faber, James E; Chilian, William M; Deindl, Elisabeth et al. (2014) A brief etymology of the collateral circulation. Arterioscler Thromb Vasc Biol 34:1854-9
Sealock, Robert; Zhang, Hua; Lucitti, Jennifer L et al. (2014) 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 114:660-71
Bastiaansen, Antonius J N M; Ewing, Mark M; de Boer, Hetty C et al. (2013) Lysine acetyltransferase PCAF is a key regulator of arteriogenesis. Arterioscler Thromb Vasc Biol 33:1902-10

Showing the most recent 10 out of 14 publications