Table 2.

Factors involved in coupling type H vessel formation and osteogenesis.

Factors	Property	Main source/location	Effect on type H vessel	Coupling effect on osteogenesis	Reference
PDGF-BB	Growth factor	Macrophage/non-resorbing osteoclast lineage cells	Induce type H vessel formation during bone modeling and remodeling	Promote the migration and differentiation of MSCs and endothelial progenitor cells; Stimulate bone formation in the ovariectomy induced osteoporotic mouse model	[340]
		Macrophage-lineage TRAP+ cells		Recruit periosteum-derived cells to the periosteal surface and direct its differentiation which contribute to cortical bone formation	[341]
VEGF-A	Growth factor	Chondrocytes; Osteoclasts; Osteoblasts	Promote type H vessel formation; However, persistent VEGFA signaling can impair PDGF-BB effects on pericytes leading to leaky blood vessels	Couple angiogenesis to enhance osteogenesis; Direct the differentiation of MSCs into osteoblast; However, high concentration of VEGF recruit osteoclast resulting in bone loss	[[342], [343], [344], [345]]
SLIT3	SLIT ligand (protein)	Osteoblast	Promote type H vessel formation	Mediate osteogenesis by regulating production of type H vessel	[346]
		Osteoclast		Promote osteoblast migration and proliferation via activating β-catenin; Suppress osteoclast differentiation and bone resorption in an autocrine manner	[347]
HIF-1α	Transcription factor	Osteoprogenitors; Osteoblast; Endothelial cell	Activation of HIF-1α signaling in ECs led to an increased formation of type H vessels	Activation of HIF-1α promote the formation of trabecular bone and increase the numbers of Runx2+ and Osterix+ osteoprogenitors; The expression of HIF-1α in ECs decreases with age, accompanied by a decrease in type H vessels and bone mass; Promote bone regeneration in a VEGF dependent manner	[335,348]
Notch (Delta-like 4)	Receptor (ligand)	Endothelial cell	Promote type H vessel formation and EC Noggin (Notch signaling activator) secretion	Promote proliferation and inhibit differentiation of mesenchymal progenitors; Promote proliferation and differentiation of osteoblasts; Activation of endothelial-cell-specific Notch signaling increase Runx2+ osteoprogenitors and osteoblastic differentiation, as well as promote chondrocyte maturation, bone growth and the formation of trabeculae	[335,342,349,350]