Occlusive vascular disease of the heart, brain and peripheral limbs is the primary cause of morbidity and mortality in the US. Angiogenesis and growth of collateral vessels are major adaptations that limit end-organ damage. Collaterals are tiny, 25 um diameter arteriole-arteriole anastomoses connecting adjacent arterial trees that are rare in number but present in most tissues. These vessels are unique -- they defy the canonical artery-capillary-venous anatomic patterning (eprhin etc), normally have little pressure drop or net flow across them, yet persist in a quiescent state despite their low/disturbed shear stress environment. When the artery supplying an adjacent tree critically narrows, collateral enlarge to endogenous bypass able to limit ischemic injury. The degree of protection depends on their pre-existing density and capacity to outwardly remodel into large 100-mmmmm diameter conduit arteries that is initiated by increased shear stress? a process termed arteriogenesis. In fact, the ability of angiogenesis to increase O2 delivery following occlusion is largely dependent on collateral remodeling. Thus, collaterals constitute a unique "third circulation" besides the arterial-venous and lymphatic circulations. Yet, compared to angiogenesis, much less is known about the mechanisms directing collateral growth. And remarkably, no studies have determined how or when collaterals develop. COL density and arteriogenesis vary widely among species and humans, suggesting a genetic basis. Yet nothing is known about the source of this variation. We have found that collaterals develop during the late embryonic-to-early postnatal period in mice. Further, we have found dramatic differences in collateral density in several in-bred mouse strains, with one strain virtually lacking a cerebral collateral circulation and thus having severe stroke and peripheral vascular disease. These findings create an excellent opportunity to identify factors and genetic polymorphisms specifying the extent of collateral formation. Our findings, using eQTL analysis and recombinant inbred and chromosome substitution mouse strain sets suggest multiple genes are involved. We have identified the first two genes that regulate collateral formation in normal tissues. One of these is also a key determinant of collateral growth/remodeling in ischemia. Identification of the factors directing collateral formation in normal tissues and potential genetic polymorphisms underlying this variation are intriguing fundamental questions. Furthermore, their answers may allow us to identify individuals at risk from too-few collaterals, as well as lead to therapies to induce formation of new collaterals: a goal that has thus far eluded investigators.