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.
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.
|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|
|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|
|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|
|Menon, Bijoy K; Smith, Eric E; Coutts, Shelagh B et al. (2013) Leptomeningeal collaterals are associated with modifiable metabolic risk factors. Ann Neurol 74:241-8|